Spiro-oxindole compounds and their use as therapeutic agents

ABSTRACT

This invention is directed to spiro-oxindole compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 37 U.S.C. §119(e) of U.S.Provisional Patent Application No. 61/106,464, filed Oct. 17, 2008,which application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to spiro-oxindole compounds andpharmaceutical compositions comprising the compounds and methods ofusing the compounds and the pharmaceutical compositions in treatingsodium channel-mediated diseases or conditions, such as pain, as well asother diseases and conditions associated with the mediation of sodiumchannels.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels, transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, are a necessary component of normal sensation, emotions, thoughtsand movements (Catterall, W. A., Nature (2001), Vol. 409, pp. 988-990).These channels consist of a highly processed alpha subunit that isassociated with auxiliary beta subunits. The pore-forming alpha subunitis sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368). Each alpha-subunitcontains four homologous domains, I to IV, each with six predictedtransmembrane segments. The alpha-subunit of the sodium channel, formingthe ion-conducting pore and containing the voltage sensors regulatingsodium ion conduction has a relative molecular mass of 260,000.Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The hallmarks of sodium channels include rapid activation andinactivation when the voltage across the plasma membrane of an excitablecell is depolarized (voltage-dependent gating), and efficient andselective conduction of sodium ions through conducting pores intrinsicto the structure of the protein (Sato, C., et al., Nature (2001),409:1047-1051). At negative or hyperpolarized membrane potentials,sodium channels are closed. Following membrane depolarization, sodiumchannels open rapidly and then inactivate. Channels only conductcurrents in the open state and, once inactivated, have to return to theresting state, favoured by membrane hyperpolarization, before they canreopen. Different sodium channel subtypes vary in the voltage range overwhich they activate and inactivate as well as their activation andinactivation kinetics.

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. Implicit with function,this family of proteins are considered prime points of therapeuticintervention. Na_(v)1.1 and Na_(v)1.2 are highly expressed in the brain(Raymond, C. K., et al., J. Biol. Chem. (2004), 279(44):46234-41) andare vital to normal brain function. In humans, mutations in Na_(v)1.1and Na_(v)1.2 result in severe epileptic states and in some cases mentaldecline (Rhodes, T. H., et al., Proc. Natl. Acad. Sci. USA(2004),101(30):11147-52; Kamiya, K., et al., J. Biol. Chem. (2004),24(11):2690-8; Pereira, S., et al., Neurology (2004), 63(1):191-2). Assuch both channels have been considered as validated targets for thetreatment of epilepsy (see PCT Published Patent Publication No. WO01/38564).

Na_(v)1.3 is broadly expressed throughout the body (Raymond, C. K., etal., op. cit.). It has been demonstrated to have its expressionupregulated in the dorsal horn sensory neurons of rats after nervoussystem injury (Hains, B. D., et al., J. Neurosci. (2003),23(26):8881-92). Many experts in the field have considered Na_(v)1.3 asa suitable target for pain therapeutics (Lai, J., et al., Curr. Opin.Neurobiol. (2003), (3):291-72003; Wood, J. N., et al., J. Neurobiol.(2004), 61(1):55-71; Chung, J. M., et al., Novartis Found Symp. (2004),261:19-27; discussion 27-31, 47-54). Na_(v)1.4 expression is essentiallylimited to muscle (Raymond, C. K., et al., op. cit.). Mutations in thisgene have been shown to have profound effects on muscle functionincluding paralysis, (Tamaoka A., Intern. Med. (2003), (9):769-70).Thus, this channel can be considered a target for the treatment ofabnormal muscle contractility, spasm or paralysis.

The cardiac sodium channel, Na_(v)1.5, is expressed mainly in the heartventricles and atria (Raymond, C. K., et al., op. cit.), and can befound in the sinovial node, ventricular node and possibly Purkinjecells. The rapid upstroke of the cardiac action potential and the rapidimpulse conduction through cardiac tissue is due to the opening ofNa_(v)1.5. As such, Na_(v)1.5 is central to the genesis of cardiacarrhythmias. Mutations in human Na_(v)1.5 result in multiple arrhythmicsyndromes, including, for example, long QT3 (LQT3), Brugada syndrome(BS), an inherited cardiac conduction defect, sudden unexpectednocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS)(Liu, H. et al., Am. J. Pharmacogenomics (2003), 3(3):173-9). Sodiumchannel blocker therapy has been used extensively in treating cardiacarrhythmias. The first antiarrhythmic drug, quinidine, discovered in1914, is classified as a sodium channel blocker.

Na_(v)1.6 encodes an abundant, widely distributed voltage-gated sodiumchannel found throughout the central and peripheral nervous systems,clustered in the nodes of Ranvier of neural axons (Caldwell, J. H., etal., Proc. Natl. Acad. Sci. USA (2000), 97(10): 5616-20). Although nomutations in humans have been detected, Na_(v)1.6 is thought to play arole in the manifestation of the symptoms associated with multiplesclerosis and has been considered as a target for the treatment of thisdisease (Craner, M. J., et al., Proc. Natl. Acad. Sci. USA (2004),101(21):8168-73).

Na_(v)1.7 was first cloned from the pheochromocytoma PC12 cell line(Toledo-Aral, J. J., et al., Proc. Natl. Acad. Sci. USA (1997),94:1527-1532). Its presence at high levels in the growth cones ofsmall-diameter neurons suggested that it could play a role in thetransmission of nociceptive information. Although this has beenchallenged by experts in the field as Na_(v)1.7 is also expressed inneuroendocrine cells associated with the autonomic system (Klugbauer,N., et al., EMBO J. (1995), 14(6):1084-90) and as such has beenimplicated in autonomic processes. The implicit role in autonomicfunctions was demonstrated with the generation of Na_(v)1.7 nullmutants; deleting Na_(v)1.7 in all sensory and sympathetic neuronsresulted in a lethal perinatal phenotype. (Nassar, et al., Proc. Natl.Acad. Sci. USA (2004), 101(34):12706-11.). In contrast, by deleting theNa_(v)1.7 expression in a subset of sensory neurons that arepredominantly nociceptive, a role in pain mechanisms, was demonstrated(Nassar, et al., op. cit.). Further support for Na_(v)1.7 blockersactive in a subset of neurons is supported by the finding that two humanheritable pain conditions, primary erythromelagia and familial rectalpain, have been shown to map to Na_(v)1.7 (Yang, Y., et al., J. Med.Genet. (2004), 41(3):171-4).

The expression of Na_(v)1.8 is essentially restricted to the DRG(Raymond, C. K., et al., op. cit.). There are no identified humanmutations for Na_(v)1.8. However, Na_(v)1.8-null mutant mice wereviable, fertile and normal in appearance. A pronounced analgesia tonoxious mechanical stimuli, small deficits in noxious thermoreceptionand delayed development of inflammatory hyperalgesia suggested to theresearchers that Na_(v)1.8 plays a major role in pain signalling(Akopian, A. N., et al., Nat. Neurosci. (1999), 2(6): 541-8). Blockingof this channel is widely accepted as a potential treatment for pain(Lai, J, et al., op. cit.; Wood, J. N., et al., op. cit.; Chung, J. M.,et al., op. cit.). PCT Published Patent Application No. WO03/037274A2describes pyrazole-amides and sulfonamides for the treatment of centralor peripheral nervous system conditions, particularly pain and chronicpain by blocking sodium channels associated with the onset or recurranceof the indicated conditions. PCT Published Patent Application No. WO03/037890A2 describes piperidines for the treatment of central orperipheral nervous system conditions, particularly pain and chronic painby blocking sodium channels associated with the onset or recurrence ofthe indicated conditions. The compounds, compositions and methods ofthese inventions are of particular use for treating neuropathic orinflammatory pain by the inhibition of ion flux through a channel thatincludes a PN3 (Na_(v)1.8) subunit.

The tetrodotoxin insensitive, peripheral sodium channel Na_(v)1.9,disclosed by Dib-Hajj, S. D., et al. (see Dib-Hajj, S. D., et al., Proc.Natl. Acad. Sci. USA (1998), 95(15):8963-8) was shown to reside solelyin the dorsal root ganglia. It has been demonstrated that Na_(v)1.9underlies neurotrophin (BDNF)-evoked depolarization and excitation, andis the only member of the voltage gated sodium channel superfamily to beshown to be ligand mediated (Blum, R., Kafitz, K. W., Konnerth, A.,Nature (2002), 419 (6908):687-93). The limited pattern of expression ofthis channel has made it a candidate target for the treatment of pain(Lai, J, et al., op. cit.; Wood, J. N., et al., op. cit.; Chung, J. M.et al., op. cit.).

NaX is a putative sodium channel, which has not been shown to be voltagegated. In addition to expression in the lung, heart, dorsal rootganglia, and Schwann cells of the peripheral nervous system, NaX isfound in neurons and ependymal cells in restricted areas of the CNS,particularly in the circumventricular organs, which are involved inbody-fluid homeostasis (Watanabe, E., et al., J. Neurosci. (2000),20(20):7743-51). NaX-null mice showed abnormal intakes of hypertonicsaline under both water- and salt-depleted conditions. These findingssuggest that the NaX plays an important role in the central sensing ofbody-fluid sodium level and regulation of salt intake behaviour. Itspattern of expression and function suggest it as a target for thetreatment of cystic fibrosis and other related salt regulating maladies.

Studies with the sodium channel blocker tetrodotoxin (TTX) used to lowerneuron activity in certain regions of the brain, indicate its potentialuse in the treatment of addiction. Drug-paired stimuli elicit drugcraving and relapse in addicts and drug-seeking behavior in rats. Thefunctional integrity of the basolateral amygdala (BLA) is necessary forreinstatement of cocaine-seeking behaviour elicited bycocaine-conditioned stimuli, but not by cocaine itself. BLA plays asimilar role in reinstatement of heroin-seeking behavior. TTX-inducedinactivation of the BLA on conditioned and heroin-primed reinstatementof extinguished heroin-seeking behaviour in a rat model (Fuchs, R. A.and See, R. E., Psychopharmacology (2002) 160(4):425-33).

This closely related family of proteins has long been recognised astargets for therapeutic intervention. Sodium channels are targeted by adiverse array of pharmacological agents. These include neurotoxins,antiarrhythmics, anticonvulsants and local anesthetics (Clare, J. J., etal., Drug Discovery Today (2000) 5:506-520). All of the currentpharmacological agents that act on sodium channels have receptor siteson the alpha subunits. At least six distinct receptor sites forneurotoxins and one receptor site for local anesthetics and relateddrugs have been identified (Cestèle, S. et al., Biochimie (2000), Vol.82, pp. 883-892).

The small molecule sodium channel blockers or the local anesthetics andrelated antiepileptic and antiarrhythmic drugs, interact withoverlapping receptor sites located in the inner cavity of the pore ofthe sodium channel (Catterall, W. A., Neuron (2000), 26:13-25). Aminoacid residues in the S6 segments from at least three of the four domainscontribute to this complex drug receptor site, with the IVS6 segmentplaying the dominant role. These regions are highly conserved and assuch most sodium channel blockers known to date interact with similarpotency with all channel subtypes. Nevertheless, it has been possible toproduce sodium channel blockers with therapeutic selectivity and asufficient therapeutic window for the treatment of epilepsy (e.g.lamotrignine, phenyloin and carbamazepine) and certain cardiacarrhythmias (e.g. lignocaine, tocamide and mexiletine). However, thepotency and therapeutic index of these blockers is not optimal and havelimited the usefulness of these compounds in a variety of therapeuticareas where a sodium channel blocker would be ideally suited.

Management of Acute and Chronic Pain

Drug therapy is the mainstay of management for acute and chronic pain inall age groups, including neonates, infants and children. The pain drugsare classified by the American Pain Society into three maincategories: 1) non-opioid analgesics-acetaminophen, and non-steroidalanti-inflammatory drugs (NSAIDs), including salicylates (e.g. aspirin),2) opioid analgesics and 3) co-analgesics.

Non-opioid analgesics such as acetaminophen and NSAIDs are useful foracute and chronic pain due to a variety of causes including surgery,trauma, arthritis and cancer. NSAIDs are indicated for pain involvinginflammation because acetaminophen lacks anti-inflammatory activity.Opioids also lack anti-inflammatory activity. All NSAIDs inhibit theenzyme cyclooxygenase (COX), thereby inhibiting prostaglandin synthesisand reducing the inflammatory pain response. There are at least two COXisoforms, COX-1 and COX-2. Common non-selective COX inhibitors include,ibuprofen and naproxen. Inhibition of COX-1, which is found inplatelets, GI tract, kidneys and most other human tissues, is thought tobe associated with adverse effects such as gastrointestinal bleeding.The development of selective COX-2 NSAIDs, such as Celecoxib, Valdecoxiband Rofecoxib, have the benefits of non-selective NSAIDs with reducedadverse effect profiles in the gut and kidney. However, evidence nowsuggests that chronic use of certain selective COX-2 inhibitors canresult in an increased risk of stroke occurrence.

The use of opioid analgesics is recommended by the American Pain Societyto be initiated based on a pain-directed history and physical thatincludes repeated pain assessment. Due to the broad adverse effectprofiles associated with opiate use, therapy should include a diagnosis,integrated interdisciplinary treatment plan and appropriate ongoingpatient monitoring. It is further recommended that opioids be added tonon-opioids to manage acute pain and cancer related pain that does notrespond to non-opioids alone. Opioid analgesics act as agonists tospecific receptors of the mu and kappa types in the central andperipheral nervous system. Depending on the opioid and its formulationor mode of administration it can be of shorter or longer duration. Allopioid analgesics have a risk of causing respiratory depression, liverfailure, addiction and dependency, and as such are not ideal forlong-term or chronic pain management.

A number of other classes of drugs may enhance the effects of opioids orNSAIDSs, have independent analgesic activity in certain situations, orcounteract the side effects of analgesics. Regardless of which of theseactions the drug has, they are collectively termed “coanalgesics”.Tricyclic antidepressants, antiepileptic drugs, local anaesthetics,glucocorticoids, skeletal muscle relaxants, anti-spasmodil agents,antihistamines, benzodiazepines, caffeine, topical agents (e.g.capsaicin), dextroamphetamine and phenothizines are all used in theclinic as adjuvant therapies or individually in the treatment of pain.The antiepeileptic drugs in particular have enjoyed some success intreating pain conditions. For instance, Gabapentin, which has anunconfirmed therapeutic target, is indicated for neuropathic pain. Otherclinical trials are attempting to establish that central neuropathicpain may respond to ion channel blockers such as blockers of calcium,sodium and/or NMDA (N-methyl-D-aspartate) channels. Currently indevelopment are low affinity NMDA channel blocking agents for thetreatment of neuropathic pain. The literature provides substantialpre-clinical electrophysiological evidence in support of the use of NMDAantagonists in the treatment of neuropathic pain. Such agents also mayfind use in the control of pain after tolerance to opioid analgesiaoccurs, particularly in cancer patients.

Systemic analgesics such as NSAIDs and opioids are to be distinguishedfrom therapeutic agents which are useful only as localanalgesics/anaesthetics. Well known local analgesics such as lidocaineand xylocalne are non-selective ion channel blockers which can be fatalwhen administered systemically. A good description of non-selectivesodium channel blockers is found in Madge, D. et al., J. Med. Chem.(2001), 44(2):115-37.

Several sodium channel modulators are known for use as anticonvulsantsor antidepressants, such as carbamazepine, amitriptyline, lamotrigineand riluzole, all of which target brain tetradotoxin-sensitive (TTX-S)sodium channels. Such TTX-S agents suffer from dose-limiting sideeffects, including dizziness, ataxia and somnolence, primarily due toaction at TTX-S channels in the brain.

Sodium Channels Role in Pain

Sodium channels play a diverse set of roles in maintaining normal andpathological states, including the long recognized role that voltagegated sodium channels play in the generation of abnormal neuronalactivity and neuropathic or pathological pain (Chung, J. M. et al., op.cit.). Damage to peripheral nerves following trauma or disease canresult in changes to sodium channel activity and the development ofabnormal afferent activity including ectopic discharges from axotomisedafferents and spontaneous activity of sensitized intact nociceptors.These changes can produce long-lasting abnormal hypersensitivity tonormally innocuous stimuli, or allodynia. Examples of neuropathic paininclude, but are not limited to, post-herpetic neuralgia, trigeminalneuralgia, diabetic neuropathy, chronic lower back pain, phantom limbpain, and pain resulting from cancer and chemotherapy, chronic pelvicpain, complex regional pain syndrome and related neuralgias.

There has been some degree of success in treating neuropathic painsymptoms by using medications, such as gabapentin, and more recentlypregabalin, as short-term, first-line treatments. However,pharmacotherapy for neuropathic pain has generally had limited successwith little response to commonly used pain reducing drugs, such asNSAIDS and opiates. Consequently, there is still a considerable need toexplore novel treatment modalities.

There remains a limited number of potent effective sodium channelblockers with a minimum of adverse events in the clinic. There is alsoan unmet medical need to treat neuropathic pain and other sodium channelassociated pathological states effectively and without adverse sideeffects. The present invention provides methods to meet these criticalneeds.

SUMMARY OF THE INVENTION

The present invention is directed to spiro-oxindole compounds andpharmaceutical compositions comprising the compounds and methods ofusing the compounds and the pharmaceutical compositions of the inventionfor the treatment and/or prevention of sodium channel-mediated diseasesor conditions, such as pain. The present invention is also directed tomethods of using the compounds of the invention and pharmaceuticalcompositions comprising the compounds of the invention for the treatmentof other sodium channel-mediated diseases or conditions, including, butnot limited to central nervous conditions such as epilepsy, anxiety,depression and bipolar disease; cardiovascular conditions such asarrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome, essentialtremour and muscle paralysis or tetanus; neuroprotection against stroke,glaucoma, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome. The presentinvention is also directed to the use of the compounds of the inventionand pharmaceutical compositions comprising the compounds of theinvention for the treatment and/or prevention of diseases or conditions,such as hypercholesterolemia, benign prostatic hyperplasia, pruritis,and cancer.

Accordingly, in one aspect, the invention is directed to compounds offormula (I):

wherein:

-   n is 1 or 2;-   one of J and K is —CH₂— and the other is —O—;-   or both J and K are each —CH₂—;-   R¹ is hydrogen, methyl, cyclopropyl, carboxymethyl,    (3-carboxy)benzyl, (3-methylsulfonylamino)benzyl,    [(3-methylsulfonylamino)pyridin-2-yl]methyl,    [(3-carboxy)pyridin-2-yl]methyl, [(ethoxy)carbonyl]methyl,    2-cyclopropylethyl, 1,3-thiazol-5-ylmethyl, 3-methoxypropyl,    (6-methylpyridin-2-yl)methyl, pyridin-3-ylmethyl,    [3-(cyano)pyridine-2-yl]methyl,    [3-(difluoromethyl)pyridin-2-yl]methyl,    3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,    4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,    [5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl,    [5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl,    [4-(trifluoromethyl)pyridin-2-yl]methyl,    (4-methyl-1,2,5-oxadiazol-3-yl)methyl, pyrazin-2-ylmethyl,    pyrimidin-2-ylmethyl, (1-methyl-1H-benzotriazol-5-yl)methyl,    [2-(tert-butoxycarbonylamino)pyridin-5-yl]methyl,    [6-(dimethylamino)pyridin-3-yl]methyl,    [6-(dimethylamino)pyridin-2-yl]methyl,    {6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl,    (5-morpholin-4-ylpyridin-2-yl)methyl,    [5-(dimethylamino)pyridin-2-yl]methyl, (6-aminopyridin-2-yl)methyl,    (6-oxo-1,6-dihydropyridin-3-yl)methyl,    (2-hydroxypyrimidin-5-yl)methyl,    (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl,    (6-aminopyridin-3-yl)methyl,    [1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl,    (5-hydroxypyridin-2-yl)methyl, (5-bromopyridin-2-yl)methyl,    hydrazinocarbonylmethyl, [6-deoxy-D-galactopyranose]-6-yl,    (6-morpholin-4-ylpyridin-3-yl)methyl,    [3-(methylsulfonyl)pyridin-2-yl]methyl,    (4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl,    (3-bromopyridin-2-yl)methyl,    [(2-imidoformamido)pyridine-5-yl]methyl,    (6-cyanopyridin-2-yl)methyl, (6-aminocarbonylpyridin-2-yl)methyl,    diphenylmethyl, 4-methoxybenzyl, 2-(fluoromethyl)benzyl,    2-ethoxyethyl, 4-fluorophenyl, (2-fluorophenylaminocarbonyl)methyl,    2-(2-methoxyethoxy)ethyl, 4-isoxazol-5-ylbenzyl,    3-(benzyloxy)propyl, (2S)-2,3-dihydroxypropyl, 4-methoxybutyl,    pentyl, isopentyl, hexyl, 3-nitrobenzyl,    [3-(trifluoromethyl)pyridin-2-yl]methyl,    [5-(trifluoromethyl)pyridin-2-yl]methyl,    [(tert-butoxycarbonylamino)pyridin-2-yl]methyl,    (3-(trifluoromethyl)pyridin-2-yl)methyl,    (5-(trifluoromethyl)furan-2-yl)methyl, tetrahydrofuran-2-ylmethyl,    3-methylbutyl, cyanomethyl, 4-hydroxybenzyl, 3-cyanobenzyl,    4-fluoro-3-methoxybenzyl, 4-cyanobenzyl,    [6-(trifluoromethyl)pyridin-3-yl]methyl,    [4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl,    (3-fluoropyridin-2-yl)methyl, (4-fluoropyridin-2-yl)methyl,    (5-fluoropyridin-3-yl)methyl, (5-fluoropyridin-2-yl)methyl,    (3-chloropyridin-2-yl)methyl, (3,5-difluoropyridin-2-yl)methyl,    (3-pyridin-3-ylisoxazol-5-yl)methyl,    (2,2-difluorocyclopropyl)methyl, 2-oxobutyl,    2,1,3-benzothiadiazol-5-ylmethyl, 2,1,3-benzoxadiazol-5-ylmethyl,    1,3-benzothiazol-2-ylmethyl, (1-methyl-1H-benzimidazol-2-yl)methyl,    [2-(1-methylethyl)-1,3-thiazol-4-yl]methyl, tert-butoxycarbonyl,    [1-(tert-butoxycarbonyl)piperidin-4-yl]methyl,    (2-methoxypyrimidin-5-yl)methyl, (6-methoxypyridin-3-yl)methyl,    (1-oxydopyridin-2-yl)methyl, (3-aminopyridin-2-yl)methyl,    piperidin-4-ylmethyl, [1-(1-methylethyl)piperidin-4-yl]methyl,    (1-methylpiperidin-4-yl)methyl, morpholin-2-ylmethyl,    [4-(1-methylethyl)morpholin-2-yl]methyl,    (4-methylmorpholin-2-yl)methyl, (2S)-morpholin-2-ylmethyl,    [(2S)-4-methylmorpholin-2-yl]methyl,    [5-(difluoromethyl)furan-2-yl]methyl,    tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl,    (5-chloro-1-methyl-1H-imidazol-2-yl)methyl,    (6-chloropyridin-2-yl)methyl, (4,6-dimethoxypyrimidin-2-yl)methyl,    [(3-methylaminocarbonyl)pyridin-2-yl]methyl,    1-[2-(aminoethyl)aminocarbonylpyridin-3-yl]methyl,    pyridin-2-ylmethyl, (2R)-1,4-dioxan-2-ylmethyl,    1,4-dioxan-2-ylmethyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,    3-hydroxypropyl, 3-phthalimidopropyl, 3-aminobenzyl,    (3-aminocarbonyl)benzyl, (4-aminocarbonyl)benzyl,    (3-N,N-dimethylaminocarbonyl)benzyl, 4-(benzyloxy)benzyl,    4-fluorobenzyl, 2,3-difluorobenzyl, 3,5-difluorobenzyl,    2-chloro-4-fluorobenzyl, [3-(2-fluorophenyl)aminocarbonyl]benzyl,    3-(methoxycarbonyl)benzyl, 4-(methoxycarbonyl)benzyl,    4-(ethoxycarbonyl)benzyl, 3-(dimethylamino-sulfonyl)benzyl,    3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl,    4-(3-amino-1H-pyrazol-5-yl)benzyl,    4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl,    3-(morpholin-4-ylsulfonyl)benzyl, 2-(difluoromethyl)benzyl,    (3-trifluoromethoxy)benzyl, (2-fluoro-6-trifluoromethyl)benzyl,    (2-fluoro-5-trifluoromethyl)benzyl, (2-trifluoromethoxy)benzyl,    3-(amino(hydroxyimino)methyl)benzyl, 2-amino-2-(hydroxyimino)ethyl,    (6-(N′-hydroxyformimidamido)pyridin-3-yl)methyl,    2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl,    (4-benzylmorpholin-2-yl)methyl, [(2S)-4-benzylmorpholin-2-yl]methyl,    2,3-dihydro-1,4-benzodioxin-6-ylmethyl,    [5-(trifluoromethyl)furan-2-yl]methyl, 3-(trifluoromethyl)benzyl,    [3-(trifluoromethyl)pyrazin-2-yl]methyl,    [4-(trifluoromethyl)pyridin-3-yl]methyl,    (5-methoxycarbonylfuran-2-yl)methyl, 5-carboxyfuran-2-ylmethyl,    5-(dimethylaminocarbonyl)furan-2ylmethyl,    [2-(trifluoromethyl)pyridin-3-yl]methyl, methylcarbonyl,    ethoxycarbonyl, tert-butoxycarbonyl or    [(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl;-   each R² is independently hydrogen, hydroxy, amino,    (hexanylaminocarbonyl)amino, (cyclopentylaminocarbonyl)amino,    benzylamino, (cyclohexylaminocarbonyl)amino, methylsulfonylamino,    (methyl)carbonylamino, N,N-dimethylaminocarbonyl,    (ethyl)carbonylamino, (butyl)carbonylamino,    (tert-butyl)carbonylamino, (pentanyl)carbonylamino,    (hexanyl)carbonylamino, (methoxymethyl)carbonylamino,    cyclobutylcarbonylamino, [2-methoxy(ethoxymethyl)]carbonylamino,    (methylsulfonyl)amino, (2-trifluoromethylphenyl)carbonylamino,    (cyclohexanyl)carbonylamino, (cyclopentanyl)carbonylamino,    (cyclopropanyl)carbonylamino, (phenyl)carbonylamino, bromo, cyano,    fluoro, methyl, methoxy, hydroxycarbonyl, methylcarbonyl,    pyrrolidinylcarbonyl, aminocarbonyl, methylaminocarbonyl,    (2-methoxyethyl)aminocarbonyl, (cyclopropyl)aminocarbonyl,    pentylaminocarbonyl, (cyclobutyl)aminocarbonyl,    (cyclopentyl)aminocarbonyl, hexanylaminocarbonyl,    (cyclohexyl)aminocarbonyl, (4-fluorophenyl)aminocarbonyl,    (4-fluorobenzyl)aminocarbonyl, (pyridin-2-ylmethyl)aminocarbonyl,    2-(2-methoxyethoxy)ethoxy, [3-(trifluoromethyl)pyridin-2-yl]oxyl,    quinolinyl, phenoxycarbonyl, 2-oxochromenyl, 2-oxopyrrolidinyl,    morpholinyl, 2-oxopyridinyl, benzyloxyl,    [3-(trifluoromethyl)pyridin-2-yl]methoxy, pyridine-2-ylmethoxy,    pyridin-2-yloxy, 4-(trifluoromethyl)phenoxy,    2-methyl-1,3-thiazol-4-yl, 2-amino-1,3-thiazol-4-yl,    6-(dimethylamino)pyridin-3-yl, furan-3-yl, 1H-pyrazol-3-yl,    1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,    5-hydroxy-1H-pyrazol-3-yl, 5-methyl-1,2,4-oxadiazol-3-yl,    (6-methoxypyridin-3-yl)oxy, 1,3-benzodioxol-5-yloxy,    4-fluorobenzyloxy, 3,5-dimethylisoxazol-4-yl, phenoxy,    3-methoxyphenoxy, 4-methoxyphenoxy, 3-morpholin-4-ylphenoxy,    4-fluorophenoxy, 4-methoxyphenyl or 4-phenoxyphenyl;-   or two adjacent R²'s, together with the adjacent carbons to which    they are attached, form a fused thiazolyl ring, a fused pyridyl ring    or a fused dioxinyl ring;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(II):

wherein:

-   each R^(3a) is hydrogen or fluoro;-   R³ is hydrogen, methyl, 3-(trifluoromethyl)pyridin-2-yl]methyl,    2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl,    (3-isopropylisoxazol-5-yl)methyl, (4-bromo-2-thienyl)methyl,    1-benzofuran-2-ylmethyl,    [2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl,    [5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl]methyl,    [5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl,    5-methoxypyridin-3-yl, 4-bromobenzyl,    [(2S)-5-oxopyrrolidin-2-yl]methyl, cyanomethyl,    [5-(trifluoromethyl)-2-furyl]methyl, (5-chloro-2-thienyl)methyl,    (3-chlorothiophen-2-yl)methyl,    [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methyl,    {2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl,    (5-phenyl-1,3,4-oxadiazol-2-yl)methyl,    [5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl,    [1,3]oxazolo[4,5-b]pyridin-2-ylmethyl,    (2-isopropyl-1,3-thiazol-5-yl)methyl,    (2-isopropyl-1,3-oxazol-5-yl)methyl,    3-(tert-butoxycarbonylamino)-3-(cyclopropyl)propyl,    4-(methylsulfanyl)benzyl, 2-cyanoethyl,    (2-bromo-1,3-thiazol-5-yl)methyl,    [2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl,    (2-amino-1,3-thiazol-4-yl)methyl, (5-chlorothiophen-2-yl)methyl,    [2-(1-methylethyl)-1,3-thiazol-4-yl]methyl,    (5-chloro-1,2,4-thiadiazol-3-yl)methyl,    (5-chloro-1,2,4-thiadiazol-3-yl)methyl, 4-methoxybenzyl,    (2S)-1,4-dioxan-2-ylmethyl, (2-chloro-1,3-thiazol-5-yl)methyl,    [2-(dimethylamino)-1,3-thiazol-5-yl]methyl,    (2-morpholin-4-yl-1,3-thiazol-5-yl)methyl,    (2-piperidin-1-yl-1,3-thiazol-5-yl)methyl,    (2-methoxy-1,3-thiazol-5-yl)methyl,    2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl,    [5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl,    (5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl,    [5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]methyl,    (5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl,    [5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl,    (4-methylpiperazin-1-yl)methyl,    (3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl,    2-(1-(methylethyl)aminocarbonylpiperidin-3-yl)ethyl,    (4-cyanothien-2-yl)methyl,    [5-trifluoromethyl-4-(methyl)aminocarbonylfuran-2-yl]methyl,    (5-trifluoromethyl-4-aminocarbonylfuran-2-yl)methyl,    [5-trifluoromethyl-4-(dimethyl)aminocarbonylfuran-2-yl]methyl,    [4-(cyclopropyl)aminocarbonyl-1,3-oxazol-2-yl]methyl,    (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl, or    [4-(methylethyl)aminocarbonyl-1,3-oxazol-2-yl]methyl;-   each R⁴ is independently hydrogen, chloro, bromo, trifluoromethyl,    cyano, 6-(dimethylamino)pyridin-3-yl, tetrahydrofuran-3-yl or    furan-3-yl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(III):

wherein:

-   m is 1 or 2;-   one of L and M is —CH₂— and the other is —O—;-   R⁵ is hydrogen, methyl, pyridazin-4-ylmethyl, diphenylmethyl,    4-methoxybenzyl, 4-hydroxybenzyl,    (5-(trifluoromethyl)furan-2-yl)methyl,    tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl,    tetrahydro-2H-pyran-3-ylmethyl,    (2-chloro-1-methyl-1H-imidazol-5-yl)methyl,    (2R)-tetrahydrofuran-2-ylmethyl, (2S)-tetrahydrofuran-2-ylmethyl,    tetrahydrofuran-3-ylmethyl, tetrahydrofuran-2-ylmethyl,    3-methylbutyl, pentyl, 5-(methoxycarbonyl)furan-2-yl,    1,4-dioxan-2-ylmethyl,    [1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl,    4-methoxycarbonyl-1,3-oxazol-2-yl, 2-fluorobenzyl, 4-fluorobenzyl,    benzyl, 4-phenylbenzyl, (3-bromoisoxazol-5-yl)methyl,    (5-bromofuran-2-yl)methyl, oxetan-2-ylmethyl,    (1-ethyl-1H-imidazol-5-yl)methyl, 3-cyanobenzyl, 4-cyanobenzyl,    4-(2-cyanophenyl)benzyl, 2-[(benzyloxy)methoxy]propyl,    2,3-dihydro-1,4-benzodioxin-6-ylmethyl,    2,1,3-benzoxadiazol-5-ylmethyl, 2,1,3-benzothiadiazol-5-ylmethyl,    (4-benzylmorpholin-2-yl)methyl,    [1-(tert-butoxycarbonyl)pyrrolidin-3-yl]methyl,    [(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]methyl,    [1-(tert-butoxycarbonyl)piperidin-4-yl]methyl,    [5-(trifluoromethyl)furan-2-yl]methyl, pyridin-2-ylmethyl,    4-(methylsulfanyl)benzyl, (2-methoxypyrimidin-5-yl)methyl,    (2R)-1,4-dioxan-2-ylmethyl, 2-(2-methoxyethoxy)ethyl,    [(2S)-5-oxopyrrolidin-2-yl]methyl,    2-(2-oxo-1,3-oxazolidin-3-yl)ethyl, 4-pyridin-2-ylbenzyl,    pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, pyrazin-2-ylmethyl,    (7-fluoro-1-benzofuran-2-yl)methyl, pyridazin-3-ylmethyl,    (2-oxo-1,3-oxazolidin-5-yl)methyl, 3-(benzyloxy)benzyl,    (1-methyl-1H-benzimidazol-2-yl)methyl, 2H-benzotriazol-2-ylmethyl,    2-methoxycarbonylbenzyl, 4-methoxycarbonylbenzyl,    3-(benzyloxy)propyl, piperidin-4-ylmethyl,    [1-(1-methylethyl)piperidin-4-yl]methyl,    (1-ethylpiperidin-4-yl)methyl, (1-methylpiperidin-4-yl)methyl,    (2S)-pyrrolidin-2-ylmethyl, 3-carboxybenzyl, 2-carboxybenzyl,    4-carboxybenzyl, 4-(benzyloxy)benzyl,    4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl,    4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,    (5-pyridin-4-ylfuran-2-yl)methyl, 4-pyridin-3-ylbenzyl,    (2′-fluorobiphenyl-4-yl)methyl,    3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,    3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl,    4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl, 3-hydroxypropyl,    morpholin-2-ylmethyl, (4-methylmorpholin-2-yl)methyl,    [4-(1-methylethyl)morpholin-2-yl]methyl, 4-(1H-tetrazol-5-yl)benzyl,    3-hydroxybenzyl, 4-morpholin-4-ylbenzyl, pyrrolidin-3-ylmethyl,    [1-((1-methylethyl)aminocarbonyl)pyrrolidin-3-yl]methyl,    [(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl,    3-(cyclohexylamino)carboxylbenzyl,    3-[(2-methoxyethyl)amino]carbonylbenzyl,    3-[(hexyl)(methyl)amino]carbonylbenzyl,    3-[(2-ethylbutyl)amino]carbonylbenzyl,    3-[(2,4-dimethylphenyl)amino]carbonylbenzyl,    3-[(2-phenylpropyl)amino]carbonylbenzyl,    3-[((1S)-1-cyclohexylethyl)amino]carbonylbenzyl,    3-[((1R)-1-cyclohexylethyl)amino]carbonylbenzyl,    2-[(4-ethylphenyl)amino]carbonylbenzyl,    2-[(2-ethylphenyl)amino]carbonylbenzyl,    2-[(2,4-dimethylphenyl)amino]carbonylbenzyl,    2-[(2-methoxyphenyl)amino]carbonylbenzyl,    2-[(2-fluorophenyl)amino]carbonylbenzyl,    2-[(3-chlorophenyl)amino]carbonylbenzyl,    2-[(3-fluoro-2-methylphenyl)amino]carbonylbenzyl,    2-[(heptyl)amino]carbonylbenzyl,    2-[(2-chlorobenzyl)amino]carbonylbenzyl,    2-(piperidin-1-yl)carbonylbenzyl, 2-[(butyl)amino]carbonylbenzyl,    2-[(3-methylphenyl)amino]carbonylbenzyl,    2-[(2-fluoro-5-methylphenyl)amino]carbonylbenzyl,    2-[(2,3-dimethylphenyl)amino]carbonylbenzyl,    2-[(2-(4-methoxyphenyl)ethyl)amino]carbonylbenzyl,    2-[(3-chlorobenzyl)amino]carbonylbenzyl,    2-[(2-(4-chlorophenyl)ethyl)amino]carbonylbenzyl,    4-[(2-methoxyphenyl)amino]carbonylbenzyl,    4-[(2-trifluoromethylphenyl)amino]carbonylbenzyl,    4-[(phenyl)amino]carbonylbenzyl, 4-[(methyl)amino]carbonylbenzyl,    4-[(2-fluorophenyl)amino]carbonylbenzyl,    4-[(2-thiophen-2-ylethyl)amino]carbonylbenzyl,    4-(amino)carbonylbenzyl,    4-[(2,3-dihydro-1H-inden-5-yl)amino]carbonylbenzyl,    4-(morpholin-1-yl)carbonylbenzyl,    4-[(2-ethylphenyl)amino]carbonylbenzyl,    4-[(2,6-dimethylphenyl)amino]carbonylbenzyl,    4-[(3-fluorophenyl)amino]carbonylbenzyl,    4-[(2,4-dimethylphenyl)amino]carbonylbenzyl,    4-[(thien-2-ylmethyl)amino]carbonylbenzyl,    4-[(ethyl)amino]carbonylbenzyl,    4-[(2-methoxyethyl)amino]carbonylbenzyl,    4-[(2-ethoxyethyl)amino]carbonylbenzyl,    4-[(cyclobutyl)amino]carbonylbenzyl,    4-[(1,3-thiazol-2-yl)amino]carbonylbenzyl,    4-[(3-fluoro-2-methylphenyl)amino]carbonylbenzyl,    4-[(2-ethylbutyl)amino]carbonylbenzyl, (aminocarbonyl)methyl,    [((4-ethylphenyl)amino)carbonyl]methyl,    [((2,5-dimethylphenyl)amino)carbonyl]methyl,    [(diethylamino)carbonyl]methyl,    [(3,3-dimethylbutylamino)carbonyl]methyl,    [(3-(1-methylethoxy)propylamino)carbonyl]methyl;    [(propylamino)carbonyl]methyl,    [(phenyl)(methyl)aminocarbonyl]methyl,    [((2,4-dimethylphenyl)amino)carbonyl]methyl,    [((2,3-dimethylphenyl)amino)carbonyl]methyl,    [((2,6-dimethylphenyl)amino)carbonyl]methyl,    (5-carboxyfuran-2-yl)methyl,    [5-(dimethylaminocarbonyl)furan-2-yl]methyl,    [5-(methylaminocarbonyl)furan-2-yl]methyl,    [4-(aminocarbonyl)-1,3-oxazol-2-yl]methyl,    [4-((dimethylamino)carbonyl)-1,3-oxazol-2-yl]methyl,    2-hydroxypropyl, (2S)-2-hydroxypropyl, 2-(benzyloxy)propyl,    2-(4-fluorobenzyloxy)propyl, 2-(pyridin-2-yloxy)propyl,    3-hydroxybutyl, 4,4,4-trifluoro-3-hydroxybutyl, 3-aminopropyl,    3-oxopropyl, 3-[(3-methylbutyl)amino]propyl,    3-[butyl(methyl)amino]propyl, 3-[(2,2,2-trifluoroethyl)amino]propyl,    3-[(2-trifluoromethoxyphenyl)carbonylamino]propyl or    3-[(2-cyanoethyl)amino]propyl; and-   each R⁶ is independently hydrogen, chloro, bromo, fluoro, methyl,    cyano, amino, —C(O)H, —CH₂—N(CH₃)₂, (pyrrolidin-1-yl)methyl,    6-(dimethylamino)pyridin-3-yl, 2-(4-fluorophenyl)ethenyl,    dibenzo[b,d]thiophen-4-yl, benzothiophen-3-yl,    1-methyl-1H-indol-5-yl, 3,5-di(trifluoromethyl)phenyl,    4-phenoxyphenyl, 4-(2-methylpropoxy)phenyl, 4-butoxyphenyl,    4-methoxyphenyl, pyrimidin-5-yl or furan-3-yl;-   or two R⁶'s, together with the adjacent carbons to which they are    attached, form a fused dioxinyl ring or a fused pyridinyl ring;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(IV):

wherein:

-   q is 1, 2 or 3;-   R⁷ is hydrogen, (5-chloro-2-thienyl)methyl,    2-(2-methoxyethoxy)ethyl, diphenylmethyl, 4-methoxybenzyl,    3-methylbutyl, benzyl, 4-bromobenzyl,    2,3-dihydro-1,4-benzodioxin-6-ylmethyl, 2-(trifluoromethyl)benzyl,    [3-(trifluoromethyl)pyridin-2-yl]methyl,    [5-(benzyloxy)pyridin-2-yl]methyl, piperidin-4-ylmethyl,    (1-methylpiperidin-4-yl)methyl, (5-hydroxypyridin-2-yl)methyl,    [5-(trifluoromethyl)furan-2-yl]methyl,    (2R)-tetrahydrofuran-2-ylmethyl, pyridin-2-ylmethyl,    pyridin-3-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl,    tetrahydro-2H-pyran-2-ylmethyl,    [1-(tert-butoxycarbonyl)piperidin-4-yl]methyl,    4-[(3R)-pyrrolidin-3-ylamino]benzyl or    (4-methylpiperazin-1-ylmethyl; and-   each R⁸ is independently hydrogen, hydroxy, bromo, chloro, cyano,    fluoro, methyl, trifluoroacetyl, methoxy, 1-methylethoxy,    2-methoxyethoxy, benzyloxy,    1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy, pyrrolidin-3-yloxy,    amino, sulfonylamino, methylsulfonylamino,    [(tert-butoxycarbonyl)pyrrolidin-3-yl]amino, 6-methoxypyridin-3-yl,    5-methyl-1,2,4-oxadiazol-3-yl, amino(hydroxyimino)methyl or    (pyrrolidin-3-yl)amino;-   or two R⁸ groups, together with the adjacent carbons to which they    are attached, form a fused dioxinyl ring, a fused thienyl ring, a    fused 1,1-dioxothienyl ring, a fused 1,2,5-oxadiazolyl ring, a fused    tetrahydropyranyl ring, a fused 2,3-dihydropyrazinyl ring, a fused    3-methyl-4,5-dihydroisoxazolyl ring or a fused pyrazinyl ring, and    the remaining R⁸ group, if present, is as described above;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(V):

wherein:

-   R⁹ is hydrogen, diphenylmethyl,    [5-(trifluoromethyl)furan-2-yl]methyl,    (2R)-tetrahydrofuran-2-ylmethyl, pyridin-2-ylmethyl,    (2R)-1,4-dioxan-2-ylmethyl, or (2S)-1,4-dioxan-2-ylmethyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(VI):

wherein:

-   Z is —O— or —N(H)—;-   R¹⁰ is hydrogen, 3-methylbutyl, 4-methoxybenzyl,    2-(2-methoxyethoxy)ethyl, 4-isoxazol-5-ylbenzyl,    2-(trifluoromethyl)benzyl, [3-(trifluoromethyl)pyridin-2-yl]methyl,    [4-(hydroxycarbonyl)oxazol-2-yl]methyl,    [4-(N,N-dimethylaminocarbonyl) oxazol-2-yl]methyl,    (4-cyanomethylcarbonyl)benzyl,    [5-(trifluoromethyl)furan-2-yl]methyl,    (2R)-tetrahydrofuran-2-ylmethyl, (3-fluoropyridin-2-yl)methyl,    [4-(methoxycarbonyl)oxazol-2-yl]methyl,    4-(3-amino-1H-pyrazol-5-yl)benzyl, pyridin-2-ylmethyl,    pyridin-3-ylmethyl or pyrazin-2-ylmethyl; and-   R^(10a) is hydrogen, methyl or —NH₂;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;    or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(VII):

wherein:

-   Y is —O— or —S—;-   R¹¹ is hydrogen, diphenylmethyl, 3-methylbutyl,    tetrahydro-2H-pyran-4-ylmethyl, (2R)-tetrahydrofuran-2-ylmethyl,    pyridin-2-ylmethyl or (5-chloro-1-methyl-1H-imidazol-2-yl)methyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(VIII):

wherein:

-   W is a direct bond or —CH₂—; and-   R¹² is hydrogen, diphenylmethyl, or (2R)-tetrahydrofuran-2-ylmethyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(IX):

wherein:

-   U is a direct bond or —CH₂—; and-   R¹³ is hydrogen, diphenylmethyl,    [5-(trifluoromethyl)furan-2-yl]methyl, or    (2R)-tetrahydrofuran-2-ylmethyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(X):

-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(XI):

wherein:

-   V is —O—, —N(CH₃)— or —CH₂— and Y is —N(CH₃)—-   or —CH₂—;-   or V is —N(CH₃)— or —CH₂— and Y is —O—, —N(CH₃)— or —CH₂—; and-   R¹⁴ is hydrogen, [5-(trifluoromethyl)furan-2-yl]methyl,    pyridin-2-ylmethyl, [3-(trifluoromethyl)pyridin-2-yl]methyl or    (2R)-tetrahydrofuran-2-ylmethyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(XII):

wherein:

-   R^(1a) is hydrogen or (pyridin-2-yl)methyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, this invention is directed to compounds of formula(XIII):

wherein:

-   E is —O— or —CH₂—;-   J is —O— or —CH₂—;-   U is a direct bond or —CH₂—; and-   R^(1b) is hydrogen, [3-(trifluoromethyl)pyridin-2-yl]methyl,    diphenylmethyl, or [5-(trifluoromethyl)furan-2-yl]methyl;-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In another aspect, the invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof; or as a pharmaceutically acceptable salt, solvate or prodrugthereof.

In another aspect, the invention provides methods for the treatment ofpain in a mammal, preferably a human, wherein the methods compriseadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of the invention, as set forth above, as astereoisomer, enantiomer, tautomer thereof or mixtures thereof; or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, and a pharmaceuticallyacceptable excipient.

In another aspect, the present invention provides a method for treatingor lessening the severity of a disease, condition, or disorder in amammal where activation or hyperactivity of one or more of Na_(v)1.1,Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7,Na_(v)1.8, or Na_(v)1.9 is implicated in the disease, condition ordisorder, wherein the method comprises administering to the mammal inneed thereof a therapeutically effective amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating a range ofsodium channel-mediated diseases or conditions in a mammal, for example,pain associated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, post-herpetic neuralgia, eudynia, heat sensitivity,tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associatedwith multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),diabetic neuropathy, peripheral neuropathy, arthritic, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses, familialerythromelagia, primary erythromelagia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke, glaucoma or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation, wherein the methods compriseadministering to the mammal in need thereof, preferably a human, atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating a range ofsodium channel-mediated diseases or conditions in a mammal, preferably ahuman, by the inhibition of ion flux through a voltage-dependent sodiumchannel in the mammal, wherein the methods comprise administering to themammal in need thereof a therapeutically effective amount of a compoundof the invention, as set forth above, as a stereoisomer, enantiomer,tautomer thereof or mixtures thereof, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, or a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating orpreventing hypercholesterolemia in a mammal, preferably a human, whereinthe methods comprise administering to the mammal in need thereof atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating orpreventing benign prostatic hyperplasia in a mammal, preferably a human,wherein the methods comprise administering to the mammal in need thereofa therapeutically effective amount of a compound of the invention, asset forth above, as a stereoisomer, enantiomer, tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

In another aspect, the invention provides methods of treating orpreventing pruritis in a mammal, preferably a human, wherein the methodscomprise administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, and a pharmaceuticallyacceptable excipient.

In another aspect, the invention provides methods of treating orpreventing cancer in a mammal, preferably a human, wherein the methodscomprise administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, and a pharmaceuticallyacceptable excipient.

In another aspect, the invention provides pharmaceutical therapy incombination with one or more other compounds of the invention or one ormore other accepted therapies or as any combination thereof to increasethe potency of an existing or future drug therapy or to decrease theadverse events associated with the accepted therapy. In one embodiment,the present invention relates to a pharmaceutical composition combiningcompounds of the present invention with established or future therapiesfor the indications listed in the invention.

In another aspect, this invention is directed to the use of thecompounds of the invention, as set forth above, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, or the use of apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of the invention, as set forth above, as astereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, in thepreparation of a medicament for the treatment of sodium channel-mediateddiseases or conditions in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

In addition to the foregoing, as used in the specification and appendedclaims, unless specified to the contrary, the following terms have themeaning indicated:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Formyl” refers to the —C(O)H radical.

“Hydroxy” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Trifluoromethyl” refers to the —CF₃ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted by one of the following groups:alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR⁴⁰, —OC(O)—R⁴⁰,—N(R⁴⁰)₂, —C(O)R⁴⁰, —C(O)OR⁴⁰, —C(O)N(R⁴⁰)₂, —N(R⁴⁰)C(O)OR⁴²,—N(R⁴⁰)C(O)R⁴², —N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2), —S(O)_(t)OR⁴²(where t is 1 to 2), —S(O)_(p)R⁴² (where p is 0 to 2), and—S(O)_(t)N(R⁴⁰)₂ (where t is 1 to 2) where each R⁴⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR⁴² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably two to eight carbon atoms and which is attached to the restof the molecule by a single bond, e.g., ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless statedotherwise specifically in the specification, an alkenyl group may beoptionally substituted by one of the following groups: alkyl, alkenyl,halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo, trimethylsilanyl, —OR⁴⁰, —OC(O)—R⁴⁰, —N(R⁴⁰)₂,—C(O)R⁴⁰, —C(O)OR⁴⁰, —C(O)N(R⁴⁰)₂, —N(R⁴⁰)C(O)OR⁴², —N(R⁴⁰)C(O)R⁴²,—N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2), —S(O)_(t)OR⁴² (where t is 1 to2), —S(O)_(p)R⁴² (where p is 0 to 2), and —S(O)_(t)N(R⁴⁰)₂ (where t is 1to 2) where each R⁴⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R⁴² is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single bond and to the radical groupthrough a single bond. The points of attachment of the alkylene chain tothe rest of the molecule and to the radical group can be through onecarbon or any two carbons within the chain. Unless stated otherwisespecifically in the specification, an alkylene chain may be optionallysubstituted by one of the following groups: alkyl, alkenyl, halo,haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR⁴⁰, —OC(O)—R⁴⁰, —N(R⁴⁰)₂, —C(O)R⁴⁰, —C(O)OR⁴⁰,—C(O)N(R⁴⁰)₂, —N(R⁴⁰)C(O)OR⁴², —N(R⁴⁰)C(O)R⁴², —N(R⁴⁰)S(O)_(t)R⁴² (wheret is 1 to 2), —S(O)_(t)OR⁴² (where t is 1 to 2), —S(O)_(p)R⁴² (where pis 0 to 2), and —S(O)_(t)N(R⁴⁰)₂ (where t is 1 to 2) where each R⁴⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R⁴² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, e.g.,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a single bond andto the radical group through a double bond or a single bond. The pointsof attachment of the alkenylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. Unless stated otherwise specifically in the specification, analkenylene chain may be optionally substituted by one of the followinggroups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, —OR⁴⁰,—OC(O)—R⁴⁰, —N(R⁴⁰)₂, —C(O)R⁴⁰, —C(O)OR⁴⁰, —C(O)N(R⁴⁰)₂,—N(R⁴⁰)C(O)OR⁴², —N(R⁴⁰)C(O)R⁴², —N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2),—S(O)_(t)OR⁴² (where t is 1 to 2), —S(O)_(p)R⁴² (where p is 0 to 2), and—S(O)_(t)N(R⁴)₂ (where t is 1 to 2) where each R⁴⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and eachR⁴² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may included fused orbridged ring systems. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unlessstated otherwise specifically in the specification, an aryl group may beoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁴¹—OR⁴⁰,—R⁴¹—OC(O)—R⁴⁰, —R⁴¹—N(R⁴⁰)₂, —R⁴¹—C(O)R⁴⁰, —R⁴¹—C(O)OR⁴⁰,—R⁴¹—C(O)N(R⁴⁰)₂, —R⁴¹—N(R⁴⁰)C(O)R⁴², —R⁴¹—N(R⁴⁰)C(O)R⁴²,—R⁴¹—N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2), —R⁴¹—N═C(OR⁴⁰)R⁴⁰,—R⁴¹—S(O)_(t)OR⁴² (where p is 0 to 2), and —R⁴¹—S(O)_(t)N(R⁴⁰)₂ (where tis 1 to 2) where each R⁴⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R⁴¹ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R⁴² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aralkyl” refers to a radical of the formula —R_(b)-R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. The alkylene chain part of the aralkyl radical may be optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical may be optionally substituted as described above foran aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated specifically in the specification, a cycloalkylgroup may be optionally substituted by one or more substituentsindependently selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁴¹—OR⁴⁰, —R⁴¹—OC(O)—R⁴⁰, —R⁴¹—N(R⁴⁰)₂,—R⁴¹—C(O)R⁴⁰, —R⁴¹—C(O)OR⁴⁰, —R⁴¹—C(O)N(R⁴⁰)₂, —R⁴¹—N(R⁴⁰)C(O)OR⁴²,—R⁴¹—N(R⁴⁰)C(O)R⁴², —R⁴¹—N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2),—R⁴¹—N═C(OR⁴⁰)R⁴⁰, —R⁴¹—S(O)_(t)OR⁴² (where t is 1 to 2),—R⁴¹—S(O)_(p)R⁴² (where p is 0 to 2), and —R⁴¹—S(O)_(t)N(R⁴⁰)₂ (where tis 1 to 2) where each R⁴⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R⁴¹ isindependently a direct bond or a straight or branched alkylene oralkenylene chain; and each R⁴² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. The alkylene chain and the cycloalkyl radicalmay be optionally substituted as defined above.

“Fused” refers to any ring system described herein which is fused to anexisting ring structure in the compounds of the invention. When thefused ring system is a heterocyclyl or a heteroaryl, any carbon in theexisting ring structure which becomes part of the fused ring system maybe replaced with a nitrogen.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkenylpart of the haloalkyl radical may be optionally substituted as definedabove for an alkenyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, a heterocyclyl group may beoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁴¹—OR⁴⁰,—R⁴¹—OC(O)—R⁴⁰, —R⁴¹—N(R⁴⁰)₂, —R⁴¹—C(O)R⁴⁰, —R⁴¹—C(O)OR⁴⁰,—R⁴¹—C(O)N(R⁴⁰)₂, —R⁴¹—N(R⁴⁰)C(O)OR⁴², —R⁴¹—N(R⁴⁰)C(O)R⁴²,—R⁴¹—N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2), —R⁴¹—N═C(OR⁴⁰) R⁴⁰,—R⁴¹—S(O)_(t)OR⁴² (where t is 1 to 2), —R⁴¹—S(O)_(p)R⁴² (where p is 0 to2), and —R⁴¹—S(O)_(t)N(R⁴⁰)₂ (where t is 1 to 2) where each R⁴⁰ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R⁴¹ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R⁴² isalkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen. An N-heterocyclyl radical may beoptionally substituted as described above for heterocyclyl radicals.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkylene chain of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl,pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl,quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl,thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-c]pyrimidin-4-onyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless statedotherwise specifically in the specification, a heteroaryl group may beoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,oxo, thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁴¹—OR⁴⁰,—R⁴¹—OC(O)—R⁴⁰, —R⁴¹—N(R⁴⁰)₂, —R⁴¹—C(O)R⁴⁰, —R⁴¹—C(O)OR⁴⁰,—R⁴¹—C(O)N(R⁴⁰)₂, —R⁴¹—N(R⁴⁰)C(O)OR⁴², —R⁴¹—N(R⁴⁰)C(O)R⁴²,—R⁴¹—N(R⁴⁰)S(O)_(t)R⁴² (where t is 1 to 2), —R⁴¹—N═C(OR⁴⁰)R⁴⁰,—R⁴¹—S(O)_(t)OR⁴² (where t is 1 to 2), —R⁴¹—S(O)_(p)R⁴² (where p is 0 to2), and —R⁴¹—S(O)_(t)N(R⁴⁰)₂ (where t is 1 to 2) where each R⁴⁰ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R⁴¹ is independently a direct bondor a straight or branched alkylene or alkenylene chain; and each R⁴² isalkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical may beoptionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i), whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroarylgroup. The alkylene chain part of the heteroarylalkyl radical may beoptionally substituted as defined above for an alkylene chain.

“Hydroxyalkyl” refers to a radical of the formula —R_(b)OH where R_(b)is an alkylene chain as defined above. The —OH group can be attached toany carbon in the alkylene chain. The alkylene chain part of theheteroarylalkyl radical may additionally be optionally substituted asdefined above for an alkylene chain.

“Analgesia” refers to an absence of pain in response to a stimulus thatwould normally be painful.

“Allodynia” refers to a condition in which a normally innocuoussensation, such as pressure or light touch, is perceived as beingextremely painful.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. SymposiumSeries, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of the invention beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction on the sodium channels, or binding affinity to pharmacologicallyimportant site of action on the sodium channels. Certainisotopically-labelled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵C and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reducation, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products are typically are identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itscoversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g. cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildelife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. When a functional group is described as “optionallysubstituted,” and in turn, substitutents on the functional group arealso “optionally substituted” and so on, for the purposes of thisinvention, such iterations are limited to five.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a sodiumchannel-mediated disease or condition in the mammal, preferably a human.The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, the manner of administration, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(a) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(b) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(c) relieving the disease or condition, i.e., causing regression of thedisease or condition; or

(d) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallisation. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

Also within the scope of the invention are intermediate compounds of theinvention and all polymorphs of the aforementioned species and crystalhabits thereof.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program, wherein the compounds of the inventionare named herein as derivatives of a central core structure. For complexchemical names employed herein, a substituent group is named before thegroup to which it attaches. For example, cyclopropylethyl comprises anethyl backbone with cyclopropyl substituent. In chemical structurediagrams, all bonds are identified, except for some carbon atoms, whichare assumed to be bonded to sufficient hydrogen atoms to complete thevalency.

Thus, for example, a compound of formula (I), as set forth above in theSummary of the Invention, wherein n is 1, J is —CH₂—, K is —O—, R² ishydrogen and R¹ is (2R)-tetrahydrofuran-2-ylmethyl; i.e., a compound ofthe following formula:

is named herein as1-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one.Embodiments Of The Invention

One embodiment of the invention is a compound of formula (I), as setforth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (I) whereinJ is —O— and K is —CH₂—.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   1′-methyl-2′-oxo-N-pentyl-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8R)-1-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (R)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one;-   6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one;-   2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (S)-1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   methyl    5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate;-   1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8R)-1-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic    acid;-   N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide;-   (8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile;-   5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   phenyl    1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate;-   4′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-one-   6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;-   7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;-   4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   3′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;-   3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile;-   1′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile;-   1′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile;-   (8S)-1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (S)-1-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   tert-butyl    4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)    methyl]piperidine-1-carboxylate;-   1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyrazin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[4-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetonitrile;-   ethyl    2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate;-   1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (S)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2-ethoxyethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8R)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′-(2′H)-yl)methyl]benzenesulfonamide;-   1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2-fluoro-5-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   7′-fluoro-1-′((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;-   1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1'H)-one;-   1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   tert-butyl    {5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate;-   1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-(2′H)-one;-   ethyl    (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate;-   1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   methyl    3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)    methyl]benzoate;-   1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   ethyl    4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate;-   2-[3-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione;-   2-[3-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione;-   (8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;-   6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;-   4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)acetic    acid;-   1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic    acid;-   3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;-   3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;-   2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile;-   (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide;-   1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic    acid;-   4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic    acid;-   N′-hydroxy-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)ethanimidamide;-   1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide;-   1′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3-aminobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N-{3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]phenyl}methanesulfonamide;-   1′-[(1-oxydopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]1′-(2′H)-yl)methyl]pyridine-3-carboxylic    acid;-   1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrobromide;-   N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide;-   1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   (8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide;-   N-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide    dihydrochloride;-   N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide;-   1′-methyl-4′-(2-oxo-2H-chromen-7-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(2-oxopyrrolidin-1-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide;-   N-(1′-methyl-Z-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-2-(trifluoromethyl)benzamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)methanesulfonamide;-   N-(1′-methyl-Z-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclohexanecarboxamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopentanecarboxamide;-   N-(1′-methyl-Z-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;-   N-(t-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopropanecarboxamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)benzamide;-   2-methoxy-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)pentanamide;-   2,2-dimethyl-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-4′-yl)propanamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)hexanamide;-   N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)heptanamide;-   2-(2-methoxyethoxy)-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;-   1-hexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;-   1-cyclopentyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;-   1-cyclohexyl-3-(1-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;-   N-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-cyclopentyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-cyclopropyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   1′-methyl-4′-(pyrrolidin-1-ylcarbonyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N-(2-methoxyethyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-(4-fluorobenzyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   1′-methyl-2′-oxo-N-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-(4-fluorophenyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   4′-amino-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-hydroxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(pyridin-2-yloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one-   4′-[2-(2-methoxyethoxy)ethoxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-[4-(trifluoromethyl)phenoxy]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;-   1′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile;-   1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   1′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(3,5-dimethylisoxazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   N,1′-dimethyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;-   4′-(3-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(3-morpholin-4-ylphenoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-[(6-methoxypyridin-3-yl)oxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(1,3-benzodioxol-5-yloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4-(pyridine-2-ylmethoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4-(4-fluorobenzyloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(4-fluorophenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   ethyl    2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate;-   tert-butyl    2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate;-   1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose;    1′-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   1-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-acetyl-1-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   4′-(5-hydroxy-1H-pyrazol-3-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-[4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide;-   1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide;-   1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one;-   1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrile;    or-   6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide.

Of this embodiment, another embodiment is a compound of formula (I)wherein J is —CH₂— and K is —O—.

Of this embodiment, one embodiment is the compound of formula (I) whichis

-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one.

Of this embodiment, another embodiment is a compound of formula (I)wherein both J and K are each —CH₂—.

Of this embodiment, one embodiment is a compound of formula (I) selectedfrom:

-   1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one;-   6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one; or-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (II), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (II) whereeach R^(3a) is hydrogen.

Of this embodiment, another embodiment is a compound of formula (II)where each R^(3a) is fluoro.

Of this embodiment, another embodiment is a compound of formula (II)selected from:

-   tert-butyl    4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-1′(2′H)-carboxylate;-   1′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-(1-benzofuran-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1'H)-one;-   (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile;-   7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   tert-butyl    [1-cyclopropyl-3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]carbamate;-   1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile;-   1′-[(2-bromo-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′H)-one;-   1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile;-   1′-[(2-amino-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-[(5-chlorothiophen-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′H)-one;-   1′-[(5-chlorothiophen-2-yl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile;-   1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile;-   4′-chloro-1′-[(5-chlorothiophen-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′H)-one;-   4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1'H)-one;-   4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-(4-methoxybenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-piperidin-1-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(2-methoxy-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one    hydrogen chloride;-   1′-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   N-isopropyl-3-[2-(2′-oxospiro[furo[2,3-g][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxamide;-   5-[(Z-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]thiophene-3-carbonitrile;-   2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile;-   N-Methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide;-   5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide;-   N,N-dimethyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide;-   N-cyclopropyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide;-   N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide;-   1′-[(5-chloro-2-thienyl)methyl]-4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-chloro-2-thienyl)methyl]-4′-(3-furyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;    and-   4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(3-chlorothiophen-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-([1,3]oxazolo[4,5-b]pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7S)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7R)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7S)-4′-bromo-1-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7S)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   (7R)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;-   1′-methyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one;    or-   6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrimidine-2,4(1H,3H)-dione.

Another embodiment of the invention is a compound of formula (III), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (III)wherein each R⁶ is independently hydrogen, chloro, bromo, fluoro,methyl, cyano, amino, —C(O)H, —CH₂—N(CH₃)₂, (pyrrolidin-1-yl)methyl,6-(dimethylamino)pyridin-3-yl, 2-(4-fluorophenyl)ethenyl,dibenzo[b,d]thiophen-4-yl, benzothiophen-3-yl, 1-methyl-1H-indol-5-yl,3,5-di(trifluoromethyl)phenyl, 4-phenoxyphenyl,4-(2-methylpropoxy)phenyl, 4-butoxyphenyl, 4-methoxyphenyl,pyrimidin-5-yl or furan-3-yl.

Of this embodiment, another embodiment is a compound of formula (III)wherein two R⁶'s, together with the adjacent carbons to which they areattached, form a fused dioxinyl ring or a fused pyridinyl ring.

Of this embodiment, another embodiment is a compound of formula (III)wherein L is —O— and M is —CH₂—.

Of this embodiment, one embodiment is a compound of formula (III)selected from:

-   (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1-(pyridazin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   7′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one;-   6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one;-   4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(tetrahydro-2H-pyran-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   methyl    5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate;-   1′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   methyl    2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate;-   1′-(2-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(4-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-benzyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(biphenyl-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(3-bromoisoxazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(tetrahydrofuran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(1-ethyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile;-   4-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1-yl)methyl)benzonitrile;-   4′-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrile;-   1′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(4-benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   tert-butyl    3-[(2′-oxo-5,6-dihydrospiro[benzo-[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate;-   tert-butyl    (2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate;-   tert-butyl    4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate;-   4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[4-(methylsulfanyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2-methoxypyrimidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one;-   (3R)-1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′-one;-   (3R)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   7′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   7′-fluoro-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[2-(2-methoxyethoxy)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(2H-benzotriazol-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   methyl    2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate;-   methyl    3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate;-   methyl    4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate;-   1′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   5′-fluoro-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(1-methylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic    acid;-   1′-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(5-pyridin-4-ylfuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(4-pyridin-3-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1-[(2′-fluorobiphenyl-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic    acid;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic    acid;-   1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbonitrile;-   2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde;-   4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(pyrrolidin-1-ylmethyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   N-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′1-1)-yl)methyl]pyrrolidine-1-carboxamide;-   (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3R)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3R)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   (3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-methoxyethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-hexyl-N-methyl-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-ethylbutyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,4-dimethylphenyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-phenylpropyl)benzamide;-   N-[(1S)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-[(1R)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   1′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   N-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-phenylbenzamide;-   N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   1′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1'H)-one;-   N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(3-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamide;-   N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-cyclobutyl-4-[(2-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1(2H)-yl)methyl]benzamide;-   4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide;-   N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   N-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide;-   2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-(4-ethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N,N-diethyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-[3-(1-methylethoxy)propyl]-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-propylacetamide;-   N-methyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-phenylacetamide;-   N-(2,5-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-(2,4-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-(2,3-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   N-(2,6-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide;-   5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic    acid;-   N,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide;-   N-methyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide;-   2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide;-   N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)    methyl]-1,3-oxazole-4-carboxamide;-   1′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-{(2S)-2-[(4-fluorobenzyl)oxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2S)-2-(pyridin-2-ylmethoxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-(4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal;-   1′-{3-[(3-methylbutyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-{3-[butyl(methyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   1′-{3-[(2,2,2-trifluoroethyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   3-{[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]amino}propanenitrile    hydrochloride;-   4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-[(E)-2-(4-fluorophenyl)ethenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-dibenzo[b,d]thiophen-4-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(1-benzothiophen-3-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(1-methyl-1H-indol-5-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-[3,5-bis(trifluoromethyl)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(4-butoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   4′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;    and-   4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one;-   3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one;-   2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one;-   1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione;-   1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one;-   N-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide;    or-   1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one.

Of this embodiment, another embodiment is a compound of formula (III)wherein L is —CH₂— and M is —O—.

Of this embodiment, one embodiment is a compound of formula (III)selected from:

-   1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one;-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one;    or-   1′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (IV), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (IV) whereineach R⁸ is independently hydrogen, hydroxy, bromo, chloro, cyano,fluoro, methyl, trifluoroacetyl, methoxy, 1-methylethoxy,2-methoxyethoxy, benzyloxy, 1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy,pyrrolidin-3-yloxy, amino, sulfonylamino, methylsulfonylamino,[(tert-butoxycarbonyl)pyrrolidin-3-yl]amino, 6-methoxypyridin-3-yl,5-methyl-1,2,4-oxadiazol-3-yl, amino(hydroxyimino)methyl or(pyrrolidin-3-yl)amino.

Of this embodiment, another embodiment is a compound of formula (IV)wherein two R⁸ groups, together with the adjacent carbons to which theyare attached, form a fused dioxinyl ring, a fused thienyl ring, a fused1,1-dioxothienyl ring, a fused 1,2,5-oxadiazolyl ring, a fusedtetrahydropyranyl ring, a fused 2,3-dihydropyrazinyl ring, a fused3-methyl-4,5-dihydroisoxazolyl ring or a fused pyrazinyl ring, and theremaining R⁸ group, if present, is hydrogen, hydroxy, bromo, chloro,cyano, fluoro, methyl, trifluoroacetyl, methoxy, 1-methylethoxy,2-methoxyethoxy, benzyloxy, 1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy,pyrrolidin-3-yloxy, amino, sulfonylamino, methylsulfonylamino,[(tert-butoxycarbonyl)pyrrolidin-3-yl]amino, 6-methoxypyridin-3-yl,5-methyl-1,2,4-oxadiazol-3-yl, amino(hydroxyimino)methyl or(pyrrolidin-3-yl)amino.

Of this embodiment, another embodiment is a compound of formula (IV)selected from:

-   1′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one;-   1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2′(1′H)-one;-   1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2′(1′H)-one    5,5′-dioxide;    spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2′(1′H)-one    5,5′-dioxide; or-   1-(pyridin-2-ylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2′(1′H)-one    5,5′-dioxide.-   1′-(4-methoxybenzyl)-3-methylspiro[furo[2,3-f][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one;-   5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(171)-one;-   1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-bromo-1-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-bromo-1-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   tert-butyl    3-{[1-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate;-   tert-butyl    3-[(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate;-   (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   (3R)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-bromo-1′-[1′-(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-Fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-fluoro-6-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   N-{2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}methanesulfonamide;-   6-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-hydroxy-1′-(3-methylbutyl)-5-(trifluoroacetyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   tert-butyl    (3R)-3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)amino]pyrrolidine-1-carboxylate;-   6-[(3R)-pyrrolidin-3-ylamino]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   tert-butyl    (3S)-3-[(2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy)pyrrolidine-1-carboxylate;-   6-[(3S)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   tert-butyl    (3R)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylate;-   6-[(3R)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   tert-butyl    3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate;-   (3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrogen chloride;-   (3R)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrogen chloride;-   6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile;-   1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   1-(diphenylmethyl)-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one;-   6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile;-   2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;-   5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one;    spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one;-   2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile;-   1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile;-   1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   1′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   tert-butyl    4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate;-   6-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one;-   6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   6-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   5,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   N′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide;-   6-hydroxy-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   6-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile;-   1′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;-   5,6-difluoro-1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one    hydrochloride;-   9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one;-   6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;    spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one;-   6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one;-   9-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   9-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   9-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;-   6-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one;    and-   6-chloro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (V), as setforth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (V) selectedfrom the group consisting of:

-   1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one;-   3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one;-   1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′H)-one;-   1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one;-   1′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one;    or-   1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (VI), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (VI) whereinZ is —O— or —N(H)— and R^(10a) is hydrogen or methyl.

Of this embodiment, one embodiment is a compound of formula (VI) whereinZ is —O— and R¹⁰ is methyl.

Of this embodiment, one embodiment is a compound of formula (VI) whereinZ is —N(H)— and R^(10a) is hydrogen.

Of this embodiment, one embodiment is a compound of formula (VI)selected from:

-   1′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one;-   1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one;-   1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,24]indazole-5,3′-indolin]-2′-one;-   1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   1′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-(3-methylbutyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   1′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   methyl    2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate;-   2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic    acid;-   N,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)    methyl]-1,3-oxazole-4-carboxamide;-   3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile;    or-   1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one    hydrochloride.

Of this embodiment, one embodiment is a compound of formula (VI) whereinR^(10a) is —NH₂.

Of this embodiment, one embodiment is a compound of formula (VI)selected from:

-   3-amino-1′-(4-methoxybenzyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;-   3-amino-1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one;    or-   3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (VII), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (VII)wherein Y is —O—.

Of this embodiment, another embodiment is a compound of formula (VII)wherein Y is —S—.

Of this embodiment, another embodiment is a compound of formula (VII)selected from:

-   2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one;-   1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one;-   2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one;-   2-methyl-1′-(3-methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one;-   2-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one;-   2-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one;-   2-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one;    or-   1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (VIII), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (VIII)wherein W is a direct bond.

Of this embodiment, one embodiment is a compound of formula (VIII)selected from:

-   1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione;-   1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione;    or-   1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione.

Of this embodiment, one embodiment is a compound of formula (VIII)wherein W is —CH₂—.

Of this embodiment, one embodiment is a compound of formula (VIII)selected from:

-   1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-d    lone;-   1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione;    or-   1-methyl-1′-[(2R)-tetrahydrofuran-2-yl    methyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione.

Another embodiment of the invention is a compound of formula (IX), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (IX) whereinU is a direct bond.

Of this embodiment, one embodiment is a compound of formula (IX)selected from:

-   1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione;-   3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione;-   3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione;    or-   3-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H-spiro[benzofuro[6,5-d]oxazole-7,3′-indoline]-2,2′(3H,6H)-dione.

Of this embodiment, one embodiment is a compound of formula (IX) whereinU is —CH₂—.

Of this embodiment, one embodiment is a compound of formula (IX)selected from:

-   4-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione;    or-   4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indole]-2′,3(1′H,4H)-dione.

Another embodiment of the invention is a compound of formula (X), as setforth above in the Summary of the Invention, which is1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione.

Another embodiment of the invention is a compound of formula (XI), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (XI) whereinboth V and Y are each —CH₂—.

Of this embodiment, one embodiment is a compound of formula (XI)selected from:

-   1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one;-   5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one;    or-   1-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′, 7′,    8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one.

Of this embodiment, one embodiment is a compound of formula (XI) whereinV is —O— and Y is —N(CH₃)—.

Of this embodiment, one embodiment is a compound of formula (XI)selected from:

-   1-methyl-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one    hydrochloride; or-   1-methyl-1-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one    hydrochloride.

Of this embodiment, one embodiment is a compound of formula (XI) whereinV is —N(CH₃)— and Y is —O—.

Of this embodiment, one embodiment is a compound of formula (XI) whichis4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one.

Of this embodiment, one embodiment is a compound of formula (XI) whereinV is —CH₂— and Y is —O—.

Of this embodiment, one embodiment is a compound of formula (XI)selected from:

-   1-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one;    or-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (XII), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (XII)selected from:

-   6-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione;    or-   6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione.

Another embodiment of the invention is a compound of formula (XIII), asset forth above in the Summary of the Invention.

Of this embodiment, one embodiment is a compound of formula (XIII)selected from:

-   1′-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one;-   1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4-dioxino[2,3-g][1,3]-benzodioxine-4,3′-indol]-2′(1′H)-one;-   2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one;    or-   1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one.

Another embodiment of the invention is a compound of formula (Ia):

wherein:

-   R¹⁵ is as defined for R¹, R³, R⁵, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹³ or R¹⁴    in compounds of formula (I), formula (II), formula (III), formula    (IV), formula (V), formula (VI), formula (VII), formula (VII),    formula (VIII), formula (IX) and formula (XI), respectively, as set    forth above in the Summary of the Invention;-   R¹⁶ is as defined for R², R⁴ or R⁶ in compounds of formula (I),    formula (II) and formula (III), respectively, as set forth above in    the Summary of the Invention; and

is a fused ring selected from the following:

where J, K, L, M, U, V, W, Y and Z are as described as for the compoundsof formula (I), formula (III), formula (VI), formula (VII), formula(VIII), formula (IX), formula (XI) and formula (XIII), as set forthabove in the Summary of the Invention;or

is a single substituent (i.e. not a fused ring) on the phenyl ringselected from —N(R²⁶)R²⁷, —OR³⁰ or —C(O)R³¹ where R²⁶ and R²⁷ are eachindependently hydrogen, alkyl, optionally substituted aryl or optionallysubstituted heteroaryl; R³⁰ is alkyl, cycloalkyl or heterocyclyl, andR³¹ is alkyl or haloalkyl;

-   as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;-   or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is a method of treating, preventingor ameliorating a disease or a condition in a mammal, preferably ahuman, wherein the disease or condition is selected from the groupconsisting of pain, depression, cardiovascular diseases, respiratorydiseases, and psychiatric diseases, and combinations thereof, andwherein the method comprises administering to the mammal in need thereofa therapeutically effective amount of an embodiment of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post-surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, dental pain, centrally mediated pain,chronic headache, migraine headache, sinus headache, tension headache,phantom limb pain, peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia,post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis,irritable bowel syndrome, Crohns disease, pain associated with multiplesclerosis (MS), amyotrophic lateral sclerosis (ALS), diabeticneuropathy, peripheral neuropathy, arthritic, rheumatoid arthritis,osteoarthritis, atherosclerosis, paroxysmal dystonia, myastheniasyndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses, familialerythromelagia, primary erythromelagia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating orpreventing hypercholesterolemia in a mammal, preferably a human, whereinthe method comprises administering to the mammal in need thereof atherapeutically effective amount of an embodiment of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating orpreventing benign prostatic hyperplasia in a mammal, preferably a human,wherein the method comprises administering to the mammal in need thereofa therapeutically effective amount of an embodiment of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating orpreventing pruritis in a mammal, preferably a human, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating orpreventing cancer in a mammal, preferably a human, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage-dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof.

Specific embodiments of the compounds of the invention are described inmore detail below in the Preparation of the Compounds of the Invention.

Utility and Testing of the Compounds of the Invention

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, especially in ahuman. Any such modulation, whether it be partial or complete inhibitionor prevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards, inhibit the voltage-dependent activity of the sodium channel,and/or reduce or prevent sodium ion flux across a cell membrane bypreventing sodium channel activity such as ion flux.

The compounds of the invention inhibit the ion flux through avoltage-dependent sodium channel. Preferably, the compounds are state orfrequency dependent modifiers of the sodium channels, having a lowaffinity for the rested/closed state and a high affinity for theinactivated state. These compounds are likely to interact withoverlapping sites located in the inner cavity of the sodium conductingpore of the channel similar to that described for other state-dependentsodium channel blockers (Cestèle, S., et al., op. cit.). These compoundsmay also be likely to interact with sites outside of the inner cavityand have allosteric effects on sodium ion conduction through the channelpore.

Any of these consequences may ultimately be responsible for the overalltherapeutic benefit provided by these compounds.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, preferably humans, and other organisms, including all thosehuman diseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

The present invention therefore relates to compounds, pharmaceuticalcompositions and methods of using the compounds and pharmaceuticalcompositions for the treatment of sodium channel-mediated diseases inmammals, preferably humans and preferably diseases related to pain,central nervous conditions such as epilepsy, anxiety, depression andbipolar disease; cardiovascular conditions such as arrhythmias, atrialfibrillation and ventricular fibrillation; neuromuscular conditions suchas restless leg syndrome and muscle paralysis or tetanus;neuroprotection against stroke, neural trauma and multiple sclerosis;and channelopathies such as erythromyalgia and familial rectal painsyndrome, by administering to a mammal, preferably a human, in need ofsuch treatment an effective amount of a sodium channel blockermodulating, especially inhibiting, agent.

Accordingly, the present invention provides a method for treating amammal for, or protecting a mammal from developing, a sodiumchannel-mediated disease, especially pain, comprising administering tothe mammal, especially a human, in need thereof, a therapeuticallyeffective amount of a compound of the invention or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention wherein the compound modulates the activity of one ormore voltage-dependent sodium channels.

The general value of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described below in the Biological Assays section.Alternatively, the general value of the compounds in treating conditionsand diseases in humans may be established in industry standard animalmodels for demonstrating the efficacy of compounds in treating pain.Animal models of human neuropathic pain conditions have been developedthat result in reproducible sensory deficits (allodynia, hyperalgesia,and spontaneous pain) over a sustained period of time that can beevaluated by sensory testing. By establishing the degree of mechanical,chemical, and temperature induced allodynia and hyperalgesia present,several physiopathological conditions observed in humans can be modeledallowing the evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allimetric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm®, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g. opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittent claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelagia, primaryerythromelagia, rectal pain, cancer, epilepsy, partial and general tonicseizures, febrile seizures, absence seizures (petit mal), myoclonicseizures, atonic seizures, clonic seizures, Lennox Gastaut, West Syndome(infantile spasms), multiresistant seizures, seizure prophylaxis(anti-epileptogenic), familial Mediterranean fever syndrome, gout,restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection underischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, reflex sympathetic dystrophy, brachial plexus avulsion,neurogenic bladder, acute pain (e.g. musculoskeletal and post-operativepain), chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, familialhemiplegic migraine, conditions associated with cephalic pain, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,pain following stroke, thalamic lesions, radiculopathy, HIV pain,post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome andpain associated with bowel disorders and dyspepsia, and combinationsthereof.

Sodium channel blockers have clinical uses in addition to pain. Epilepsyand cardiac arrhythmias are often targets of sodium channel blockers.Recent evidence from animal models suggest that sodium channel blockersmay also be useful for neuroprotection under ischaemic conditions causedby stroke or neural trauma and in patients with multiple sclerosis (MS)(Clare, J. J. et al., op. cit. and Anger, T. et al., op. cit.).

The present invention also relates to compounds, pharmaceuticalcompositions and methods of using the compounds and pharmaceuticalcompositions for the treatment or prevention of diseases or conditionssuch as benign prostatic hyperplasia (BPH), hypercholesterolemia, cancerand pruritis (itch).

Benign prostatic hyperplasia (BPH), also known as benign prostatichypertrophy, is one of the most common diseases affecting aging men. BPHis a progressive condition which is characterized by a nodularenlargement of prostatic tissue resulting in obstruction of the urethra.Consequences of BPH can include hypertrophy of bladder smooth muscle, adecompensated bladder, acute urinary retention and an increasedincidence of urinary tract infection.

BPH has a high public health impact and is one of the most commonreasons for surgical intervention among elderly men. Attempts have beenmade to clarify the etiology and pathogenesis and, to that end,experimental models have been developed. Spontaneous animal models arelimited to the chimpanzee and the dog. BPH in man and the dog share manycommon features. In both species, the development of BPH occursspontaneously with advanced age and can be prevented byearly/prepubertal castration. A medical alternative to surgery is verydesirable for treating BHP and the consequences.

The prostatic epithelial hyperplasia in both man and the dog is androgensensitive, undergoing involution with androgen deprivation and resumingepithelial hyperplasia when androgen is replaced. Cells originating fromthe prostate gland have been shown to express high levels of voltagegated sodium channels. Immunostaining studies clearly demonstratedevidence for voltage gated sodium channels in prostatic tissues(Prostate Cancer Prostatic Dis. 2005; 8(3):266-73).

Hypercholesterolemia, i.e., elevated blood cholesterol, is anestablished risk factor in the development of, e.g., atherosclerosis,coronary artery disease, hyperlipidemia, stroke, hyperinsulinemias,hypertension, obesity, diabetes, cardiovascular diseases (CVD),myocardial ischemia, and heart attack. Thus, lowering the levels oftotal serum cholesterol in individuals with high levels of cholesterolhas been known to reduce the risk of these diseases. The lowering of lowdensity lipoprotein cholesterol in particular is an essential step inthe prevention of CVD. Although there are a variety ofhypercholesterolemia therapies, there is a continuing need and acontinuing search in this field of art for alternative therapies.

The invention provides compounds which are useful asantihypercholesterolemia agents and their related conditions. Thepresent compounds may act in a variety of ways. While not wishing to bebound to any particular mechanism of action, the compounds may be director indirect inhibitors of the enzyme acyl CoA: cholesterol acyltransferase (ACAT) that results in inhibition of the esterification andtransport of cholesterol across the intestinal wall. Another possibilitymay be that the compounds of the invention may be direct or indirectinhibitors of cholesterol biosynthesis in the liver. It is possible thatsome compounds of the invention may act as both direct or indirectinhibitors of ACAT and cholesterol biosynthesis.

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritis are complex and poorly understood,there has long been acknowledged to have interactions with pain. Inparticular, it is believed that sodium channels likely communicate orpropagate along the nerve axon the itch signals along the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

From a neurobiology level, it is believed that there is a sharedcomplexity of specific mediators, related neuronal pathways and thecentral processes of itch and pain and recent data suggest that there isa broad overlap between pain- and itch-related peripheral mediatorsand/or receptors (Ikoma et al., Nature Reviews Neuroscience, 7:535-547,2006). Remarkably, pain and itch have similar mechanisms of neuronalsensitization in the peripheral nervous system and the central nervoussystem but exhibits intriguing differences as well.

For example, the mildly painful stimuli from scratching are effective inabolishing the itch sensation. In contrast, analgesics such as opioidscan generate severe pruritus. The antagonistic interaction between painand itch can be exploited in pruritus therapy, and current researchconcentrates on the identification of common targets for futureanalgesic and antipruritic therapy.

Compounds of the present invention have been shown to have analgesiceffects in a number of animal models at oral doses ranging from 1 mg/Kgto 100 mg/Kg. The compounds of the invention can also be useful fortreating pruritus.

The types of itch or skin irritation, include, but are not limited to:

a) psoriatic pruritis, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof;

b) itch caused by allergic reactions, insect bites, hypersensitivity(e.g., dry skin, acne, eczema, psoriasis), inflammatory conditions orinjury;

c) itch associated with vulvar vestibulitis; and d) skin irritation orinflammatory effect from administration of another therapeutic such as,for example, antibiotics, antivirals and antihistamines.

The compounds of the invention are also useful in treating or preventingcertain hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer,thyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal Na_(v)1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. 2005, Aug. 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically Na_(v)1.7, is associated with strong metastatic potentialin prostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73).

The compounds of the invention are also useful in treating or preventingsymptoms in a mammal associated with BPH such as, but not limited to,acute urinary retention and urinary tract infection.

The compounds of the invention are also useful in treating or preventingcertain endocrine imbalances or endocrinopathies such as congenitaladrenal hyperplasia, hyperthyroidism, hypothyroidism, osteoporosis,osteomalacia, rickets, Cushing's Syndrome, Conn's syndrome,hyperaldosteronism, hypogonadism, hypergonadism, infertility, fertilityand diabetes.

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.measuring current, measuring membrane potential, measuring ion flux,(e.g. sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

A competitive binding assay with known sodium channel toxins such astetrodotoxin, alpha-scorpion toxins, aconitine, BTX and the like, may besuitable for identifying potential therapeutic agents with highselectivity for a particular sodium channel. The use of BTX in such abinding assay is well known and is described in McNeal, E. T., et al.,J. Med. Chem. (1985), 28(3):381-8; and Creveling, C. R., et al., Methodsin Neuroscience, Vol. 8: Neurotoxins (Conn PM Ed) (1992), pp. 25-37,Academic Press, New York.

These assays can be carried out in cells, or cell or tissue extractsexpressing the channel of interest in a natural endogenous setting or ina recombinant setting. The assays that can be used include plate assayswhich measure Na+ influx through surrogate markers such as ¹⁴C-guanidineinflux or determine cell depolarization using fluorescent dyes such asthe FRET based and other fluorescent assays or a radiolabelled bindingassay employing radiolabelled aconitine, BTX, TTX or STX. More directmeasurements can be made with manual or automated electrophysiologysystems. The guanidine influx assay is explained in more detail below inthe Biological Assays section.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available, however these are of only limitedfunctional value and information content. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive²²-[Na] and ¹⁴[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (AuroraBiosciences Corporation, San Diego, Calif., a division of VertexPharmaceuticals, Inc.) which may be used in conjunction with FRET dyes,also available from Aurora Biosciences. This assay measures sub-secondresponses to voltage changes. There is no requirement for a modifier ofchannel function. The assay measures depolarization andhyperpolarizations, and provides ratiometric outputs for quantification.A somewhat less expensive MTS version of this assay employs theFLEXstation™ (Molecular Devices Corporation) in conjunction with FRETdyes from Aurora Biosciences. Other methods of testing the compoundsdisclosed herein are also readily known and available to those skilledin the art.

These results provide the basis for analysis of the structure-activityrelationship (SAR) between test compounds and the sodium channel.Certain substituents on the core structure of the test compound tend toprovide more potent inhibitory compounds. SAR analysis is one of thetools those skilled in the art may now employ to identify preferredembodiments of the compounds of the invention for use as therapeuticagents.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as arrhythmias and epilepsy, benignprostatic hyperplasia (BPH), hypercholesterolemia, cancer and pruritis(itch) with minimal adverse events. The assays described below in theBiological Assays Section are useful in assessing the biologicalactivity of the instant compounds.

Typically, a successful therapeutic agent of the present invention willmeet some or all of the following criteria. Oral availability should beat or above 20%. Animal model efficacy is less than about 0.1 μg toabout 100 mg/Kg body weight and the target human dose is between 0.1 μgto about 100 mg/Kg body weight, although doses outside of this range maybe acceptable (“mg/Kg” means milligrams of compound per kilogram of bodymass of the subject to whom it is being administered). The therapeuticindex (or ratio of toxic dose to therapeutic dose) should be greaterthan 100. The potency (as expressed by IC₅₀ value) should be less than10 μM, preferably below 1 μM and most preferably below 50 nM. The IC₅₀(“Inhibitory Concentration—50%”) is a measure of the amount of compoundrequired to achieve 50% inhibition of ion flux through a sodium channel,over a specific time period, in an assay of the invention. Compounds ofthe present invention in the guanidine influx assay have demonstratedIC₅₀'s ranging from less than a nanomolar to less than 10 micromolar.

In an alternative use of the invention, the compounds of the inventioncan be used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting Na_(v)1.1,Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7,Na_(v)1.8, or Na_(v)1.9 activity in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula I or a composition comprising said compound. The term“biological sample”, as used herein, includes, without limitation, cellcultures or extracts thereof; biopsied material obtained from a mammalor extracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

Inhibition of Na_(v)1.1, Na_(v)1.2, Na_(v)1.3, Na_(v)1.4, Na_(v)1.5,Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, or Na_(v)1.9 activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of sodium ion channels in biological and pathologicalphenomena; and the comparative evaluation of new sodium ion channelinhibitors.

The compounds of the invention, as set forth above in the Summary of theInvention, as stereoisomers, enantiomers, tautomers thereof or mixturesthereof, or pharmaceutically acceptable salts, solvates or prodrugsthereof, and/or the pharmaceutical compositions described herein whichcomprise a pharmaceutically acceptable excipient and one or morecompounds of the invention, as set forth above in the Summary of theInvention, as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, can be used in the preparation of a medicament for thetreatment of sodium channel-mediated disease or condition in a mammal.

Pharmaceutical Compositions of the Invention and Administration

The present invention also relates to pharmaceutical compositioncontaining the compounds of the invention disclosed herein. In oneembodiment, the present invention relates to a composition comprisingcompounds of the invention in a pharmaceutically acceptable carrier,excipient or diluent and in an amount effective to modulate, preferablyinhibit, ion flux through a voltage-dependent sodium channel to treatsodium channel mediated diseases, such as pain, when administered to ananimal, preferably a mammal, most preferably a human patient.

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see The Science and Practice ofPharmacy, 20th Edition (Philadelphia College of Pharmacy and Science,2000). The composition to be administered will, in any event, contain atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, for treatment of a disease orcondition of interest in accordance with the teachings of thisinvention.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in REMINGTON′S PHARMACEUTICAL SCIENCES(Mack Pub. Co., N.J. current edition).

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 Kg mammal) from about0.001 mg/Kg (i.e., 0.07 mg) to about 100 mg/Kg (i.e., 7.0 g); preferablya therapeutically effective dose is (for a 70 Kg mammal) from about 0.01mg/Kg (i.e., 0.7 mg) to about 50 mg/Kg (i.e., 3.5 g); more preferably atherapeutically effective dose is (for a 70 Kg mammal) from about 1mg/Kg (i.e., 70 mg) to about 25 mg/Kg (i.e., 1.75 g).

The ranges of effective doses provided herein are not intended to belimiting and represent preferred dose ranges. However, the mostpreferred dosage will be tailored to the individual subject, as isunderstood and determinable by one skilled in the relevant arts. (see,e.g., Berkow et al., eds., The Merck Manual, 16^(th) edition, Merck andCo., Rahway, N.J., 1992; Goodmanetna., eds., Goodman and Cilman's ThePharmacological Basis of Therapeutics, 10^(th) edition, Pergamon Press,Inc., Elmsford, N.Y., (2001); Avery's Drug Treatment: Principles andPractice of Clinical Pharmacology and Therapeutics, 3rd edition, ADISPress, LTD., Williams and Wilkins, Baltimore, Md. (1987), Ebadi,Pharmacology, Little, Brown and Co., Boston, (1985); Osolci al., eds.,Remington's Pharmaceutical Sciences, 18^(th) edition, Mack PublishingCo., Easton, Pa. (1990); Katzung, Basic and Clinical Pharmacology,Appleton and Lange, Norwalk, Conn. (1992)).

The total dose required for each treatment can be administered bymultiple doses or in a single dose over the course of the day, ifdesired. Generally, treatment is initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. The diagnostic pharmaceutical compound orcomposition can be administered alone or in conjunction with otherdiagnostics and/or pharmaceuticals directed to the pathology, ordirected to other symptoms of the pathology. The recipients ofadministration of compounds and/or compositions of the invention can beany vertebrate animal, such as mammals. Among mammals, the preferredrecipients are mammals of the Orders Primate (including humans, apes andmonkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs),Rodenta (including mice, rats, rabbits, and hamsters), and Carnivora(including cats, and dogs). Among birds, the preferred recipients areturkeys, chickens and other members of the same order. The mostpreferred recipients are humans.

For topical applications, it is preferred to administer an effectiveamount of a pharmaceutical composition according to the invention totarget area, e.g., skin surfaces, mucous membranes, and the like, whichare adjacent to peripheral neurons which are to be treated. This amountwill generally range from about 0.0001 mg to about 1 g of a compound ofthe invention per application, depending upon the area to be treated,whether the use is diagnostic, prophylactic or therapeutic, the severityof the symptoms, and the nature of the topical vehicle employed. Apreferred topical preparation is an ointment, wherein about 0.001 toabout 50 mg of active ingredient is used per cc of ointment base. Thepharmaceutical composition can be formulated as transdermal compositionsor transdermal delivery devices (“patches”). Such compositions include,for example, a backing, active compound reservoir, a control membrane,liner and contact adhesive. Such transdermal patches may be used toprovide continuous pulsatile, or on demand delivery of the compounds ofthe present invention as desired.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems include osmotic pump systemsand dissolutional systems containing polymer-coated reservoirs ordrug-polymer matrix formulations. Examples of controlled release systemsare given in U.S. Pat. Nos. 3,845,770 and 4,326,525 and in P. J. Kuzmaet al., Regional Anesthesia 22 (6): 543-551 (1997), all of which areincorporated herein by reference.

The compositions of the invention can also be delivered throughintra-nasal drug delivery systems for local, systemic, and nose-to-brainmedical therapies. Controlled Particle Dispersion (CPD)™ technology,traditional nasal spray bottles, inhalers or nebulizers are known bythose skilled in the art to provide effective local and systemicdelivery of drugs by targeting the olfactory region and paranasalsinuses.

The invention also relates to an intravaginal shell or core drugdelivery device suitable for administration to the human or animalfemale. The device may be comprised of the active pharmaceuticalingredient in a polymer matrix, surrounded by a sheath, and capable ofreleasing the compound in a substantially zero order pattern on a dailybasis similar to devises used to apply testosterone as described in PCTPublished Patent Application No. WO 98/50016.

Current methods for ocular delivery include topical administration (eyedrops), subconjunctival injections, periocular injections, intravitrealinjections, surgical implants and iontophoresis (uses a small electricalcurrent to transportionized drugs into and through body tissues). Thoseskilled in the art would combine the best suited excipients with thecompound for safe and effective intra-occular administration.

The most suitable route will depend on the nature and severity of thecondition being treated. Those skilled in the art are also familiar withdetermining administration methods (e.g., oral, intravenous, inhalation,sub-cutaneous, rectal etc.), dosage forms, suitable pharmaceuticalexcipients and other matters relevant to the delivery of the compoundsto a subject in need thereof.

Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

-   -   opiates analgesics, e.g. morphine, heroin, cocaine, oxymorphine,        levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,        propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,        meripidine, methadone, nalorphine, naloxone, naltrexone,        buprenorphine, butorphanol, nalbuphine and pentazocine;    -   non-opiate analgesics, e.g. acetomeniphen, salicylates (e.g.        aspirin);    -   nonsteroidal antiinflammatory drugs (NSAIDs), e.g. ibuprofen,        naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac,        diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,        flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,        meclofenamic acid, mefenamic acid, meloxicam, nabumetone,        naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,        phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and        zomepirac;    -   anticonvulsants, e.g. carbamazepine, oxcarbazepine, lamotrigine,        valproate, topiramate, gabapentin and pregabalin;    -   antidepressants such as tricyclic antidepressants, e.g.        amitriptyline, clomipramine, despramine, imipramine and        nortriptyline;    -   COX-2 selective inhibitors, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib;    -   alpha-adrenergics, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, and        4-amino-6,7-dimethoxy-2-(5-methane        sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   barbiturate sedatives, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal and thiopental;    -   tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g.        (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl)ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   coal-tar analgesics, in particular paracetamol;    -   serotonin reuptake inhibitors, e.g. paroxetine, sertraline,        norfluoxetine (fluoxetine desmethyl metabolite), metabolite        demethylsertraline, 3 fluvoxamine, paroxetine, citalopram,        citalopram metabolite desmethylcitalopram, escitalopram,        d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,        litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and        fluoxetine;    -   noradrenaline (norepinephrine) reuptake inhibitors, e.g.        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®)),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine, and venlafaxine        duloxetine neuroleptics sedative/anxiolytics;    -   dual serotonin-noradrenaline reuptake inhibitors, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   acetylcholinesterase inhibitors such as donepezil;    -   5-HT₃ antagonists such as ondansetron;    -   metabotropic glutamate receptor (mGluR) antagonists;    -   local anaesthetic such as mexiletine and lidocaine;    -   corticosteroid such as dexamethasone;    -   antiarrhythimics, e.g. mexiletine and phenyloin;    -   muscarinic antagonists, e.g., tolterodine, propiverine, tropsium        t chloride, darifenacin, solifenacin, temiverine and        ipratropium;    -   cannabinoids;    -   vanilloid receptor agonists (e.g. resinferatoxin) or antagonists        (e.g. capsazepine);    -   sedatives, e.g. glutethimide, meprobamate, methaqualone, and        dichloralphenazone;    -   anxiolytics such as benzodiazepines,    -   antidepressants such as mirtazapine,    -   topical agents (e.g. lidocaine, capsacin and resiniferotoxin);    -   muscle relaxants such as benzodiazepines, baclofen,        carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and        orphrenadine;    -   anti-histamines or H1 antagonists;    -   NMDA receptor antagonists;    -   5-HT receptor agonists/antagonists;    -   PDEV inhibitors;    -   Tramadol®;    -   cholinergic (nicotinc) analgesics;    -   alpha-2-delta ligands;    -   prostaglandin E2 subtype antagonists;    -   leukotriene B4 antagonists;    -   5-lipoxygenase inhibitors; and    -   5-HT₃ antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

Kits-of-Parts

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the invention. Thekit also includes instructions for the use of the pharmaceuticalcomposition for modulating the activity of ion channels, for thetreatment of pain, as well as other utilities as disclosed herein.Preferably, a commercial package will contain one or more unit doses ofthe pharmaceutical composition. For example, such a unit dose may be anamount sufficient for the preparation of an intravenous injection. Itwill be evident to those of ordinary skill in the art that compoundswhich are light and/or air sensitive may require special packagingand/or formulation. For example, packaging may be used which is opaqueto light, and/or sealed from contact with ambient air, and/or formulatedwith suitable coatings or excipients.

Preparation of the Compounds of the Invention

The compounds of the invention are prepared by the methods disclosedherein and by methods similar to those described in PCT Published PatentApplication, WO 2006/110917 and to those described in PCT PublishedPatent Application WO 2008/046049, the disclosures of which are bothincorporated in full herein in their entireties, particularly withrespect to the methods of preparation disclosed therein with respect tothe compounds disclosed therein.

It is also understood that one skilled in the art would be able to makein a similar manner as described below the compounds of the invention byreference to the disclosures of PCT Published Patent Application, WO2006/110917 by using the appropriate starting materials and modifyingthe parameters of the synthesis as needed. In general, startingcomponents may be obtained from sources such as Sigma Aldrich, LancasterSynthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA,etc., or synthesized according to sources known to those skilled in theart (see, e.g., Smith, M. B. and J. March, Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 5th edition (Wiley, December2000)), or may be prepared as described in PCT Published PatentApplication, WO 2006/110917, or may be prepared by methods disclosedherein.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (2006),4^(th) Ed., Wiley. The protecting group may also be a polymer resin suchas a Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

All of the compounds described below as being prepared which may existin free base or acid form may be converted to their pharmaceuticallyacceptable salts by treatment with the appropriate inorganic or organicbase or acid. Salts of the compounds prepared below may be converted totheir free base or acid form by standard techniques. It is understoodthat all polymorphs, amorphous forms, anhydrates, hydrates, solvates andsalts of the compounds of the invention are intended to be within thescope of the invention. Furthermore, all compounds of the inventionwhich contain an acid or an ester group can be converted to thecorresponding ester or acid, respectively, by methods known to oneskilled in the art or by methods described herein.

Alternatively, the compounds of the invention can be synthesizedfollowing the procedures set forth below in REACTION SCHEMES 1-27 where,unless indicated otherwise, q is 1 or 2, each X is halo, preferablybromo or chloro, R″ is an alkyl group, R¹⁵ is as defined for R¹, R^(1a),R^(1b), R³, R⁵, R⁷, R⁹, R¹⁹, R¹¹, R¹², R¹³ or R¹⁴ in compounds offormula (I), formula (II), formula (III), formula (IV), formula (V),formula (VI), formula (VII), formula (VII), formula (VIII), formula(IX), formula (XI), formula (XII) and formula (XIII), R¹⁶ is as definedfor R², R⁴ or R⁶ in compounds of formula (I), formula (II) and formula(III), and

is defined as one of the following:

where J, K, L, M, U, V, W, Y and Z are as described as for the compoundsof formula (I), formula (III), formula (VI), formula (VII), formula(VIII), formula (IX), formula (XI) and formula (XIII).Preparation of Compounds of Formula (Ia), Formula (Iaa) and Formula(Iab)

Compounds of formula (Ia), formula (Iaa) and formula (Iab) are compoundsof the invention, as set forth above in the Summary of the Invention.They may be prepared by the methods set forth below in REACTION SCHEMES1 and 2 below where R^(50a), R^(50b), R^(50c) and R^(50d) are eachindependently hydrogen, hydroxy, bromo, chloro, cyano, fluoro, methyl,trifluoroacetyl, methoxy, 1-methylethoxy, 2-methoxyethoxy, benzyloxy,1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy, pyrrolidin-3-yloxy, amino,sulfonylamino, methylsulfonylamino,[(tert-butoxycarbonyl)pyrrolidin-3-yl]amino, 6-methoxypyridin-3-yl,5-methyl-1,2,4-oxadiazol-3-yl, amino(hydroxyimino)methyl or(pyrrolidin-3-yl)amino; or R^(50a) and R^(50b), or R^(50b) and R^(50c),or R^(50c) and R^(50d), together with the adjacent carbons to which theyare attached, form a fused dioxinyl ring, a fused thienyl ring, a fused1,1-dioxothienyl ring, a fused 1,2,5-oxadiazolyl ring, a fusedtetrahydropyranyl ring, a fused 2,3-dihydropyrazinyl ring, a fused3-methyl-4,5-dihydroisoxazolyl ring or a fused pyrazinyl ring, and theremaining R^(50a), R^(50b), R^(50c) and R^(50d) group, if present, is asdescribed above:

Compounds of formula (101), formula (102), formula (104), formula (105),formula (110), and formula (112) are commercially available or can beprepared according to methods known to one skilled in the art or by themethods disclosed herein or by the methods disclosed in PCT PublishedPatent Application WO 2006/110917.

As set forth above, compounds of formula (Ia) are prepared by firstalkylating an isatin compound of formula (101) with the chloro or bromocompound of formula (102) to afford the product of formula (103).Alternatively, an indole compound of formula (110) is iodinated withiodine and alkylated with the chloro or bromo compound of formula (102)to afford the product of formula (111). Oxidation of (111) withruthenium (III) chloride monohydrate and sodium periodate gives theisatin product of formula (103). Alternatively, treatment of an anilinecompound of formula (112) with oxalyl chloride gives the istain compoundof formula (103). The phenol compound of formula (104) is treated with aGrignard reagent of formula (105) at low temperature (0° C.) to form thephenoxymagnesium halide intermediate which reacts with the keto-carbonylgroup of the isatin compound of formula (103) in a solvent, such as, butnot limited to, methylene chloride or tetrahydrofuran, to afford theoxindole of formula (106). The compound of formula (107) is obtainedafter the removal of the hydroxyl group at C-3 position of the oxindoleby treating the compound of formula (106) with a silane such as, but notlimited to, triethylsilane. The compound of formula (107) can also beachieved by treating the compound of formula (106) with thionylchloride/triethylamine then reduction with zinc dust. The compound offormula (107) is treated with an alkylating reagent such as, but notlimited to, chloroiodomethane or 1,2-dibromoethane with a base, such as,but not limited to, cesium carbonate, in a solvent, such as, but notlimited to, tetrahydrofuran or N,N-dimethylformamide to afford thecompound of formula (Ia) of the invention via intramolecularcyclization. Alternatively, compound (107) is treated with a silylcompound, such as, but not limited to, trimethylsilyl chloride togenerate a silyl ether intermediate which is treated with ytterbium(III) trifluoromethanesulfonate and formaldehyde to afford the compoundof formula (108). The compound of formula (108) can also be obtained bytreating the compound of formula (107) with a base, such as, but notlimited to, LiOH, iPr₂NH, LDA and subsequently reacting withformaldehyde. Intramolecular cyclization of the compound of formula(108) via Mitsunobu reaction in the presence of a phosphine reagent suchas, but not limited to, triphenylphosphine, tributylphosphine, ortrimethylphosphine, and azadicarboxylate of diethyl, diisopropyl ordi-tert-butyl, or N,N,N′,N′-tetramethylazodicarboxamide in a solventsuch as, but not limited to, tetrahydrofuran, ethyl acetate, ordichloromethane, affords the compound of formula (Ia) of the invention.

Compounds of formula (Ia), (Iaa) and (Iab) can also be prepared by themethod illustrated below in REACTION SCHEME 2 where q, R¹⁵, R¹⁶,R^(50a), R⁵⁰, R^(50c) and R^(50d) are as defined above, and PG is anitrogen-protecting group:

Compounds of formula (203), formula (204), formula (205), formula (206)and formula (207) are commercially available or can be preparedaccording to methods known to one skilled in the art or by methodsdisclosed herein.

Compounds of formula (201) where PG is a nitrogen-protecting group suchas, but not limited to, diphenylmethyl, are synthesized through thesequence as shown in REACTION SCHEME 1 above. When the protecting groupis diphenylmethyl, it is removed under a high pressure of hydrogen suchas 60-120 psi to form the oxindole compound of formula (202); it canalso be removed by the treatment of compound of formula (201) withtriethyl silane and trifluoroacetic acid at 70° C. to 100° C. Theformation of the compound of formula (Ia) is achieved by alkylation ofthe compound of formula (202) with an alkylating reagent R¹⁵—X (203),where X is chloro, bromo, iodo, or OTs, alternatively, when X is chloro,the reagent is generated from the corresponding alcohol (204) byreacting with a chlorinating reagent such as, but not limited to,thionyl chloride or N-(chloromethylene)-N-methylmethanaminium chloride(Vilsmeier reagent)) in the presence of a base such as, but not limitedto, sodium hydride, sodium bis(trimethylsilyl)amide, lithium hydroxide,or cesium carbonate, in a solvent such as, but not limited to,N,N-dimethylformamide, tetrahydrofuran, 2-butanone, acetone,acetonitrile or the combination of any two of them, in the presence orabsence of potassium iodide.

Alternatively, reaction of compound of formula (202) with an alcohol(204) under Mitsunobu reaction conditions in the presence of a phosphinereagent such as, but not limited to, triphenylphosphine,tributylphosphine, or trimethyl phosphine, and azadicarboxylate ofdiethyl, diisopropyl, di-tent-butyl orN,N,N′,N′-tetramethylazodicarboxamide in a solvent such as, but notlimited to, tetrahydrofuran, ethyl acetate, or dichloromethane, providesthe compound of formula (Ia).

Alternatively, reaction of compound of formula (202) with a boronic acid(205) in the presence of a copper reagent such as, but not limited to,cupric acetate, and 4-(N,N-dimethylamino)pyridine, a base such as, butnot limited to, sodium hexamethyldisilazide in a solvent such as, butnot limited to, toluene provides the compound of formula (Ia).

Alternatively, when R¹⁵ is an aryl or heteroaryl group in compound(203), compound (203) reacts with compound (202) in the presence of apalladium catalyst such as, but not limited to, palladium (II) acetate,a ligand such as, but not limited to,9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and a base such as, butnot limited to, cesium carbonate in a solvent such as, but not limitedto, 1,4-dioxane to provide the product of formula (Ia).

In general, treatment of compound of formula (202) with a base such as,but not limited to, sodium hydride or triethylamine, and a chloroformatereagent such as, but not limited to, ethyl chloroformate ordi-tert-butyl dicarbonate provides the carbamate compound of formula(Iaa). Treatment of compound of formula (202) with an acylating reagentsuch as, but not limited to, acetic anhydride provides the compound offormula (Iab).

Preparation of Compounds of Formula (Ib) and Formula (Ic)

Compounds of formula (Ib) and (Ic) are compounds of the invention, asset forth above in the Summary of the Invention. They may be prepared bythe methods set forth below in REACTION SCHEME 3 where

is a N-heterocycly, PG is nitrogen protecting group, q and R¹⁶ and

are as defined above, R¹⁷ and R¹⁸ are each independently hydrogen oralkyl, and R¹⁹ is hydrogen, alkyl or aryl:

Compounds of formula (301) can be prepared according to methods known toone skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.Compounds of formula (303) and formula (305) are commercially availableor can be prepared according to methods known to one skilled in the art.

In general, compounds of formula (Ib) and formula (Ic) are prepared bythe procedure set forth above in REACTION SCHEME 3 by deprotection ofcompounds of formula (301) using methods known to one skilled in the artto generate the compounds of formula (302). Reductive amination of (302)with an aldehyde or a ketone (303) in the presence of a reducing agentsuch as, but not limited to, sodium cyanoborohydride or sodiumtriacetoxyborohydride, or alternatively with formaldehyde and formicacid in refluxing water, provides the amine compound of formula (Ic).

In another aspect, the urea compounds of formula (Ib) are prepared bytreating an amine compound of formula (302) with an isocyanate in thepresence of a base, such as, but not limited to, triethylamine ordiisopropylethylamine, in a solvent such as, but not limited to,dichloromethane or chloroform.

Preparation of Compounds of Formula (Id)

Compounds of formula (Id) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 4 where q and R¹⁶ and

are as defined above, Q is an alkylene chain, an aralkyl group, or aheteroarylalkyl group (where —CN is a substituent on the aryl radical ofthe aralkyl group or on the heteroaryl radical of the heteroarylalkylgroup) and R²⁰ is hydrogen, alkyl, haloalkyl or cycloalkyl:

Compounds of formula (401) can be prepared according to methods known toone skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

REACTION SCHEME 4 illustrates a schematic synthesis of oxadiazolecompounds for formula (Id). Compounds of formula (402) can be obtainedby treating the compound of formula (401) with hydroxylamine in asolvent such as, but not limited to, dimethyl sulfoxide. A compound offormula (402) is converted to a compound of formula (Id) by reactingwith an appropriately substituted anhydride or acyl chloride in thepresence of a base such as, but not limited to, pyridine (also as asolvent) in a microwave reactor at a high temperature such as 170° C.Alternatively, the oxadiazole ring formation is accomplished by reactingcompound (402) with an appropriately substituted anhydride or acylchloride in the presence of a base such as, but not limited to,diisopropylamine, in a solvent such as, but not limited to,dichloromethane.

Alternatively, a compound of formula (402) can react with anappropriately substituted acyl chloride in the presence of a base suchas, but not limited to, diisopropyl amine, in a solvent such as, but notlimited to, dichloromethane to lead to the formation of compound offormula (403), which is then treated with a base such as, but notlimited to, pyridine (also as a solvent) in a microwave reactor at ahigh temperature such as 170° C. to provide the compound of formula(Id).

Preparation of Compounds of Formula (Ie) and Formula (if)

Compounds of formula (Ie) and formula (If) are compounds of theinvention, as set forth above in the Summary of the Invention. They maybe prepared by the methods set forth below in REACTION SCHEME 5 where q,R¹⁶ and

are as defined above,

is a N-heteroaryl, and R²¹ and R²² are each independently hydrogen,alkyl, aralkyl, or aryl or R²¹ and R²², together with the nitrogen towhich they are both attached, form an optionally substitutedN-heteroaryl or N-heterocycle:

Compounds of formula (501) can be prepared according to methods known toone skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 5 above illustrates a schematic synthesis ofcompounds of formula (Ie) and formula (If). A compound of formula (Ie)is obtained by treating the compound of formula (501) with an amine suchas, but not limited to, dimethylamine, piperidine or morpholine in asolvent such as, but not limited to, N,N-dimethylfromamide at a hightemperature, such as 120° C.

In another aspect, compound of formula (If) is obtained by treating thecompound of formula (501) with an oxide nucleophile such as, but notlimited to, sodium methoxide in a solvent such as, but not limited to,N,N-dimethylfromamide at high temperature such as 120° C.

Preparation of Compounds of Formula (Iq)

Compounds of formula (Ig) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 6 where q, R¹⁶ and

are as defined above, Q is an alkylene chain, an aralkyl group or aheteroarylalkyl group (where —C(O)OR²³ is a substituent on the arylradical of the aralkyl group or on the heteroaryl radical of theheteroarylalkyl group), R²³ is alkyl, and R²⁴ and R²⁵ are eachindependently hydrogen, alkyl, cycloalkyl, aryl or heteroaryl:

Compounds of formula (601) can be prepared according to methods known toone skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 6 illustrates a schematic synthesis ofcompounds as formula (Ig). An ester compound of formula (601) isconverted to the corresponding carboxylic acid of formula (602) bytreatment of the ester compound of formula (601) with a base such as,but not limited to, lithium hydroxide, sodium hydroxide or potassiumhydroxide, in a mixed solvent such as, but not limited to,tetrahydrofuran or methanol with water. The acid compound of formula(602) can be converted to a mixed anhydride, by treatment with iso-butylchloroformate in the presence of a base such as, but not limited to,N-methylmorpholine, or the corresponding acid chloride, by treating withoxalyl chloride in the presence of catalytic amount ofN,N-dimethylformamide in a solvent such as, but not limited to, toluene,dichloromethane or chloroform. The mixed anhydride reacts directly with,or the acid chloride react with, in the presence of a base such as, butnot limited to, triethylamine or diisopropyl ethylamine, a primary orsecondary amine to form the amide compound (603). When R²⁴ and R²⁵ areeach hydrogen, the compound of formula (603) reacts withN,N-dimethylacetamide dimethyl acetyl in a solvent such as, but notlimited to, 1,4-dioxane to generate an intermediate that reacts withhydrazine to form the triazole compound of (Ig).

Preparation of Compounds of Formula (Ih), Formula (II), Formula (IIa),Formula (IIb), Formula (Iic), Formula (ID, Formula (Ik), Formula (Ika),Formula (Ikb), Formula (Ikc), Formula (Ikd), Formula (Ike) and Formula(Ikf)

Compounds of formula (Ih), formula (Ii), formula (Iia), formula (Iib),formula (Iic), formula (IA formula (Ik), formula (Ika), formula (Ikb),formula (Ikc), formula (Ikd), formula (Ike) and formula (Ikf) arecompounds of the invention, as set forth above in the Summary of theInvention. They may be prepared by the methods set forth below inREACTION SCHEMES 7 and 8 wherein q, R¹⁵, R¹⁶, R²⁰, and

are as defined above,

is aryl or heteroaryl, R²⁶, R²⁷, and R²⁸ are each independentlyhydrogen, alkyl, optionally substituted aryl or optionally substitutedheteroaryl, and R³⁵ is alkyl, aryl or heteroaryl:

Compounds of formula (701) and formula (801) can be prepared accordingto methods known to one skilled in the art or by the methods disclosedherein or by the methods disclosed in PCT Published Patent ApplicationWO 2006/110917.

In general, compounds of formula (Ih), formula (Ii), formula (Iia),formula (Iib), formula (Iic), formula (Ij) formula (Ik), formula (Ika),formula (Ikb), formula (Ikc), formula (Ikd), formula (Ike) and formula(Ikf) are synthesized as shown in REACTION SCHEME 7 or REACTION SCHEME8. Compound of formula (701) or formula (801) reacts with a primary orsecondary amine in the presence of a palladium catalyst such as, but notlimited to, palladium acetate, tetrakis(triphenylphosphine)palladium(0)or tris(dibenzylideneacetone)dipalladium(0) with or without a ligandsuch as, but not limited to, triphenylphosphine, tri(o-tolyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene or2-(di-tert-butylphosphino)biphenyl, a base such as, but not limited to,sodium carbonate, cesium carbonate or sodium tert-butoxide, in a solventsuch as, but not limited to, toluene, dioxane or tetrahydrofuran, toprovide the amino compound of formula (Iia) or formula (Ika) (See Muci,A. R. et al., Topics in Current Chemistry (2002), 219:131).

Alternatively, compound of formula (701) or formula (801) reacts with acyclised lactam type of compound in the presence of a copper catalystsuch as, but not limited to, copper (I) iodide, a ligand such as, butnot limited to, 8-hydroxyquinoline orrac-trans-N,N′-dimethylcyclohexane-1,2-diamine, a base such as, but notlimited to, potassium carbonate in a solvent such as, but not limitedto, dimethyl sulfoxide provides the product of formula (Iia) or formula(Ika).

Alternatively, the carboxylic acid compound of formula (702) reacts withdiphenyl phosphorazidate in the presence of an amine such as, but notlimited to, triethylamine and tert-butanol in a solvent such as, but notlimited to, toluene gives a tert-butyloxycarbonyl protected aminointermediate that leads to the formation of the amino compound offormula (Iia), where R²⁶ and R²⁷ are each hydrogen, upon acidictreatment.

Compound (701) or (801) reacts with an alkyl, vinyl, aryl or heteroarylboronic acid or an alkyl, vinyl, aryl or heteroaryl stannane reagent inthe presence of a palladium catalyst such as, but not limited to,palladium acetate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0) with or without a ligand suchas, but not limited to, triphenylphosphine, tri(o-tolyl)phosphine,1,1′-bis(diphenylphosphino)ferrocene or2-(di-tert-butylphosphino)biphenyl, a base such as, but not limited to,sodium carbonate, cesium carbonate, or sodium bicarbonate in a solventsuch as, but not limited to, dimethoxyethane, dioxane, ortetrahydrofuran to provide the coupled product of formula (Ih) or (ID(See Kotha, S. et al., Tetrahedron (2002), 58:9633 and Miyaura, N. etal., Chem. Rev. (1995), 95:2457 and Farina, V. et al., Org. React.(1997), 50:1).

Compound (701) or (801) reacts with sodium cyanide, zinc cyanide ortributyltin cyanide and potassium cyanide in the presence of a nickelcatalyst such as, but not limited to, nickel(II) chloride or a palladiumcatalyst such as, but not limited to, palladium acetate,tris(dibenzylideneacetone)dipalladium(0) and a ligand such as, but notlimited to, tri(o-tolyl)phosphine, 1,1′-bis(diphenylphosphino)ferroceneor 2-(di-tert-butylphosphino)biphenyl in a solvent such as, but notlimited to, N,N-dimethylformamide, 1-methylpyrrolidinone or acetonitrileto provide the cyano compounds of formula (Ii) or formula (Ik) (SeeMarcantonio, K. M. et al., Org. Lett. (2004), 6:3723-5 and Yang, C. etal., Org. Lett. (2004), 6:2837-40).

Compound (701) reacts with a sodium sulfonate such as, but not limitedto, sodium methanesulfonate in the presence of a copper catalyst suchas, but not limited to, copper iodide, and the sodium salt of L-prolinein a solvent such as, but not limited to, dimethyl sulfoxide to providethe sulfone product of formula (Iib).

In compound of formula (Ika), when R²⁶ and R²⁷ are each hydrogen, it iscoupled with a carboxylic acid, carried out by one skilled in the art,to provide the amide compound of formula (Ikb). Alternatively, treatmentof the amino compound of formula (Ika) with an amine in the presence ofa coupling agent such as, but not limited to, trichloromethylchloroformate provide the urea compound of formula (Ikc).

Compound (801) reacts with an alcohol and carbon monoxide in thepresence of a palladium catalyst such as, but not limited to, palladiumacetate and a ligand such as, but not limited to,1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate) and abase such as, but not limited to, potassium carbonate in a solvent suchas, but not limited to, N,N-dimethylformamide to provide the estercompound of formula (ID, where R²⁸ is —COOR²⁵ (where R²⁵ is as definedabove). When R²⁵ is phenyl, the ester compound of formula (Ij) istreated with an amine in the presence of a base such as, but not limitedto, potassium carbonate in a solvent such as, but not limited to,N,N-dimethylformamide to provide the amide compound of formula (Ikd).Alternatively, the ester compound of formula (Ij) is hydrolyzed using abase such as, but not limited to, lithium hydroxide or sodium hydroxideto afford an acid that can couple with an amine, carried out by oneskilled in the art, to provide the amide compound of formula (Ikd).Alternatively, the hydrolysis of a nitrile compound of formula (Ik) withaqueous sodium carbonate and hydrogen peroxide in a solvent such as, butnot limited to, ethanol provides the primary amide compound of formula(Ikd).

Alternatively, compounds of formula (802) can be obtained by treatingthe compound of formula (Ik) with hydroxylamine in a solvent such as,but not limited to, dimethyl sulfoxide. A compound of formula (802) isconverted to a compound of formula (Ike) by reacting with anappropriately substituted anhydride or acyl chloride in the presence ofa base such as, but not limited to, pyridine (also as a solvent) in amicrowave reactor at a high temperature such as 170° C.

Alternatively, when R²⁶ and R²⁷ are each hydrogen, compounds of formula(Iia) and (Ika) react with a sulfonyl chloride reagent such as, but notlimited to, methanesulfonyl chloride in the presence of a base such as,but not limited to, pyridine in a solvent such as, but not limited to,dichloromethane or chloroform to provide the sulphonamide product offormula (Iic) and (Ikf).

Preparation of Compounds of Formula (Im) and Formula (Ima)

Compounds of formula (Im) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 9 wherein q, R¹⁵, R¹⁶, R²⁰,R²⁶ and R²⁷ are as described above:

Compounds of formula (901) can be prepared according to methods known toone skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, compounds of formula (Im) and formula (Ima) are synthesizedas shown in REACTION SCHEME 9. A compound of formula (901) reacts with aprimary or secondary amine in the presence of a palladium catalyst suchas, but not limited to, palladium (II) acetate,tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0) with or without a ligand suchas, but not limited to, triphenylphosphine, tri(o-tolyl)phosphine,1,1-bis(diphenylphosphino)ferrocene or2-(di-tert-butylphosphino)biphenyl, a base such as, but not limited to,sodium carbonate, cesium carbonate or sodium tert-butoxide in a solventsuch as, but not limited to, toluene, dioxane, or tetrahydrofuran toprovide the amino compound of formula (Im) (See Muci, A. R. et al.,Topics in Current Chemistry (2002), 219:131).

Compound (901) reacts with sodium cyanide, zinc cyanide or tributyltincyanide and potassium cyanide in the presence of a nickel catalyst suchas, but not limited to, nickel(II) chloride or a palladium catalyst suchas, but not limited to, palladium acetate,tris(dibenzylideneacetone)dipalladium(0) and a ligand such as, but notlimited to, tri(o-tolyl)phosphine, 1,1′-bis(diphenylphosphino)ferroceneor 2-(di-tert-butylphosphino)biphenyl in a solvent such as, but notlimited to, N,N-dimethylformamide, 1-methylpyrrolidinone or acetonitrileto provide the cyano compounds of formula (902) (See Marcantonio, K. M.et al., Org. Lett. (2004), 6:3723-5 and Yang, C. et al., Org. Lett.(2004), 6:2837-40).

A compound of formula (902) is treated with hydroxylamine and with anappropriately substituted anhydride or acyl chloride in the presence ofa base such as, but not limited to, pyridine (also as a solvent) in amicrowave reactor at a high temperature such as 170° C. to provide theoxadiazole product of formula (Ima).

Preparation of Compounds of Formula (In) and (Ina)

Compounds of formula (In) and (Ina) are compounds of the invention, asset forth above in the Summary of the Invention. They may be prepared bythe methods set forth below in REACTION SCHEME 10 wherein R¹⁵, R²⁶, R²⁷and

are as defined above, and R²⁹ is —C(O)H, alkyl, hydroxyalkyl or formyl:

Compounds of formula (1001) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, compounds of formula (In) can be synthesized as shown inREACTION SCHEME 10. Treatment of a compound of formula (1001) with alithium reagent such as, but not limited to, n-butyllithium ort-butyllithium in a solvent such as, but not limited to, tetrahydrofuranor diethyl ether, generates an anion that reacts with an electrophile toprovide the compound of formula (1002). When the electrophile isN,N-dimethylformamide, an aldehyde compound of formula (1002) where R²⁹is C(O)H is obtained, which reacts with an amine under reductiveamination conditions, in the presence of a reducing agent such as, butnot limited to, sodium cyanoborohydride or sodium triacetoxyborohydride,to provide the amine compound of formula (In).

Alternatively, treatment of a compound of formula (1001) with an alcoholsuch as, but not limited to, benzyl alcohol, phenol or substituted aryland heteroaryl hydroxy compounds in the presence of a copper reagentsuch as, but not limited to, copper (I) iodide, a ligand such as, butnot limited to, 3,4,7,8-tetramethyl-1,10-phenanthroline and a base suchas, but not limited to, cesium carbonate in a solvent such as, but notlimited to, toluene provides the ether compound of formula (Ina).

Alternatively, treatment of a compound of formula (1001) with a lithiumreagent such as n-butyl lithium or t-butyl lithium, a boron reagent suchas, but not limited to, trimethyl borate, followed by oxidation withhydrogen peroxide affords the hydroxy compound of formula (1003).Treatment of a compound of formula (1003) with an aryl or heteroarylhalide in the presence of a copper reagent such as, but not limited to,copper (I) iodide, a ligand such as, but not limited to,1-butyl-1H-imidazole and a base such as, but not limited to, potassiumcarbonate in a solvent such as, but not limited to, toluene provides theether compound of formula (Ina).

Alternatively, treatment of a compound of formula (1003) with a basesuch as, but not limited to, cesium carbonate in a solvent such as, butnot limited to, N,N-dimethylformamide and reaction with a halo reagentR²⁷—X gives the ether compound of formula (Ina).

Preparation of Compounds of Formula (Io)

Compounds of formula (Io) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 11 wherein q, R¹⁵ and R¹⁶ areas defined above and R³⁰ is alkyl, cycloalkyl or heterocyclyl:

Compounds of formula (1101) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 11 illustrates a schematic synthesis ofcompounds of formula (Io). The benzyl protecting group of (1101) isremoved selectively by hydrogenation under one atm pressure of hydrogenwith a catalyst such as, but not limited to, palladium on carbon in asolvent such as, but not limited to, methanol, to provide the compoundof formula (1102). The reaction of compound of formula (1102) with analcohol (R³⁰—OH) under Mitsunobu reaction conditions in the presence ofa phosphine reagent such as, but not limited to, triphenylphosphine,tributylphosphine, or trimethyl phosphine, and azadicarboxylate ofdiethyl, diisopropyl, di-tert-butyl orN,N,N,N′-tetramethylazodicarboxamide in a solvent such as, but notlimited to, tetrahydrofuran, ethyl acetate, or dichloromethane, providesthe compound of formula (Io).

Alternatively, treatment of compound of formula (1102) with a base suchas, but not limited to, potassium carbonate or sodium hydride in asolvent such as, but not limited to N,N-dimethylformamide ortetrahydrofuran and reaction with an alkyl halide R³⁰—X provides thecompound of formula (Io).

Preparation of Compounds of Formula (Ip)

Compounds of formula (Ip) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 12 wherein R″, q, R¹⁵ and R¹⁶are as defined above, and R³¹ is alkyl or haloalkyl:

Compounds of formula (1201) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.Compounds of formula (105) are commercially available.

In general, REACTION SCHEME 12 illustrates a schematic synthesis ofcompounds of formula (Ip). Treatment of the alcohol compound of formula(1201) with a Grignard reagent of formula (105) at low temperature (0°C.) forms a phenoxymagnesium halide intermediate which reacts with anelectrophile such as, but not limited to, trifluoroacetic anhydride in asolvent, such as, but not limited to, methylene chloride ortetrahydrofuran, to afford a compound of formula (Ip).

Preparation of Compounds of Formula (Iq), Formula (Ir) and Formula (Is)

Compounds of formula (Iq), formula (Ir) and formula (Is) are compoundsof the invention, as set forth above in the Summary of the Invention.They may be prepared by the methods set forth below in REACTION SCHEME13 wherein q, R¹⁶, R²⁶, R²⁷ and

are as defined above, and Qa is an C₁-C₃alkylene chain, R³² is hydrogenor alkyl, and R³³ is hydrogen, alkyl, haloalkyl, cycloalkyl orheterocyclyl:

Compounds of formula (1301) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.Compounds R³³—X are commercially available.

In general, REACTION SCHEME 13 illustrates a schematic synthesis ofcompounds of formula (Iq), formula (Ir) and formula (Is). The oxygenprotecting group in the compound of formula (1301) is removed by usingthe method known to one skilled in the art to provide the alcoholcompound of formula (1302). Alkylation with a halide (bromo, chloro orbromo) reagent (R³³—X) in the presence of a base such as, but notlimited to, cesium carbonate, sodium hydride or potassium carbonate, ina solvent such as, but not limited to, tetrahydrofuran orN,N-dimethylformamide, provides the compound of formula (Iq). When R³²is a hydrogen in the compound of formula (1302), the primary alcohol isoxidized by an oxidant such as, but not limited to,1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1′H)-one(Dess-Martin periodinane) to form its corresponding aldehyde compound offormula (1304), which reacts with an amine under reductive aminationconditions, in the presence of a reducing agent such as, but not limitedto, sodium cyanoborohydride or sodium triacetoxyborohydride, to providethe amine compound of formula (Ir). In another aspect, the aldehydecompound of formula (1304) reacts with a nucleophile such as, but notlimited to, methyl magnesiumbromide or the combination oftrifluoromethyltrimethylsilane and cesium fluoride to form the compoundof formula (Is).

Preparation of Compounds of Formula (It)

Compounds of formula (It) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 14 wherein q, R¹⁶ and

are as defined above, and

is an optionally substituted N-heterocyclyl:

Compounds of formula (1401) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 14 illustrates a schematic synthesis ofcompounds of formula (It). Treatment of a compound of formula (1401)with formaldehyde in the presence of an optionally substitutedN-heterocyclyl, such as, but not limited to, 4-methylpiperazine orpiperidine, in a solvent such as, but not limited to, methanol, providesthe compounds of formula (It).

Preparation of Compounds of Formula (Iu)

Compounds of formula (Iu) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 15 wherein X, q, R¹⁶ and

are as defined above, and

is an optionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl and R³⁴ is alkyl or aralkyl:

Compounds of formula (1501) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.Compounds R³⁴—X are commercially available.

In general, REACTION SCHEME 15 illustrates a schematic synthesis ofcompounds of formula (Iu). Treatment of a compound of formula (1501)with a base such as, but not limited to, sodium hydride and analkylating reagent (R³⁴—X) in a solvent such as, but not limited to,tetrahydrofuran or N,N-dimethylformamide provides the compound offormula (Iu). Alternatively, the alkylation is accomplished by reactingthe compound of formula (1501) with an alkylating reagent such as, butnot limited to dimethyl sulfate under phase transfer reaction conditionsusing a base such as, but not limited to sodium hydroxide, a phasetransfer catalyst such as, but not limited to tetrabutylammonium bromidein a solvent such as, but not limited to, aqueous tetrahydrofuran toprovide the compound of formula (Iu).

Preparation of Compounds of Formula (Iv) and (Iva)

Compounds of formula (Iv) and (Iva) are compounds of the invention, asset forth above in the Summary of the Invention. They may be prepared bythe methods set forth below in REACTION SCHEME 16 wherein R¹⁵R²⁰ and

are as defined above:

Compounds of formula (1601) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 16 illustrates a schematic synthesis ofcompounds of formula (Iv) and (Iva). Treatment of a compound of formula(1601) with a vinyl ether such as, but not limited to, butyl vinyl etherin the presence of a palladium catalyst such as, but not limited to,palladium (II) acetate, a ligand such as, but not limited to,1,3-bis(diphenylphosphino)propane and a base such as, but not limitedto, potassium carbonate in a solvent such as, but not limited to,N,N-dimethylformamide provides the compound of formula (1602).Bromination of (1602) with phenyltrimethylammonium tribromide gives thebromo compound of formula (1603). Reaction of (1603) with a sulphurcontaining reagent such as, but not limited to, thioacetamide orthiourea gives the thiazole compounds of formula (Iv). Alternatively,treatment of (1602) with a strong base such as, but not limited to,sodium hydride followed by the reaction with diethyl carbonate in asolvent such as, but not limited to, tetrahydrofuran gives thedicarbonyl compound of formula (1604), which is cyclised with hydrazineto provide the pyrazole compound of formula (Iva).

Preparation of Compounds of Formula (Iw)

Compounds of formula (Iw) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 17 wherein q, R¹⁶ and

are as defined above, and

is an optionally substituted N-heteroaryl:

Compounds of formula (1701) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 17 illustrates a schematic synthesis ofcompounds of formula (Iw). Treatment of a compound of formula (1701)with N,N-dimethylformamide dimethyl acetal gives the imidoformamidecompounds of formula (1702), which upon treatment with trifluoroaceticanhydride in a solvent such as, but not limited to, tetrahydrofuranprovides the cyclized compounds of formula (Iw).

Preparation of Compounds of Formula (Ix)

Compounds of formula (Ix) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 18 where q and R¹⁶ and

are as defined above, Qb is an alkylene chain or an aralkyl group andR³⁵ is alkyl, aryl or heteroaryl:

Compounds of formula (1801) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 18 illustrates a schematic synthesis ofcompounds of formula (Ix). Treatment of a compound of formula (1801)with hydrazine gives the amino compounds of formula (1802), which uponreaction with an acylating reagent, carried out by one skilled in theart, provides the amide compound of formula (Ix).

Preparation of Compounds of Formula (Iy)

Compounds of formula (Iy) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 19 where q, R¹⁶ and

are as defined above, Q is an alkylene chain, an aralkyl group, an arylor a heteroaryl group (where —CONH₂ is a substituent on the aryl radicalof the aralkyl group and on the heteroaryl radical of theheteroarylalkyl group) and R³⁵ is alkyl, aryl or heteroaryl:

Compounds of formula (1901) and (1902) can be prepared according tomethods known to one skilled in the art or by the methods disclosedherein or by the methods disclosed in PCT Published Patent ApplicationWO 2006/110917.

In general, REACTION SCHEME 19 illustrates a schematic synthesis ofcompounds of formula (Iy). Treatment of a compound of formula (1901)with an amide acetyl such as, but not limited to, dimethylacetamidedimethyl acetal in a solvent such as, but not limited to, 1,4-dioxane,followed by reaction with hydroxylamine in the presence of acetic acidgives the oxadiazole compound of formula (Iy).

Alternatively, treatment of the acid compound of formula (1902) withoxalyl chloride in the presence of a catalytic amount ofN,N-dimethylformamide generates the corresponding acyl chloride, whichupon reaction with an amidine compound such as, but not limited to,N-hydroxyacetamidine in a solvent such as, but not limited to, pyridineprovides the oxadiazole product of formula (Iy).

Preparation of Compounds of Formula (Iz)

Compounds of formula (Iz) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 20 where q and R¹⁶ and

are as defined above, Q is an alkylene chain, an aralkyl group, an arylgroup or a heteroaryl group:

Compounds of formula (2001) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 20 illustrates a schematic synthesis ofcompounds of formula (Iz). Treatment of a compound of formula (2001)with a strong base such as, but not limited to, sodium hydride affordsthe cyano compound of formula (2002). Reaction of (2002) with hydrazinein a solvent such as, but not limited to, ethanol, provides the pyrazolecompound of formula (Iz).

Preparation of Compounds of Formula (Iza)

Compounds of formula (Iza) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 21 where q, R¹⁶, R²⁰ and

are as defined above, Qb is an alkylene chain or an aralkyl group, or anaryl or heteroaryl group and R²⁰ is alkyl, aryl or heteroaryl:

Compounds of formula (2101) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 21 illustrates a schematic synthesis ofcompounds of formula (Iza). Treatment of the ester compound of formula(2101) with hydrazine in a solvent such as, but not limited to, ethanolgives the hydrazide compound of formula (2102), which upon reaction withan appropriately substituted anhydride or acyl chloride in the presenceof a base such as, but not limited to, pyridine (also as a solvent)provides the oxadiazole product of formula (Iza).

Preparation of Compounds of Formula (Izb)

Compounds of formula (Izb) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 22 where R¹⁵ and

are as defined above:

Compounds of formula (2201) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 22 illustrates a schematic synthesis ofcompounds of formula (Izb). Treatment of the furan compound of formula(2201) with hydrogen in the presence of a palladium catalyst such as,but not limited to, palladium on carbon in a solvent such as, but notlimited to, ethyl acetate or methanol provides the tetrahydrofuranproduct of formula (Izb).

Preparation of Compounds of Formula (Izc)

Compounds of formula (Izc) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 23 where R¹⁶ and

are as defined above, and

is a a nitrogen-containing heteroaryl:

Compounds of formula (2301) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.

In general, REACTION SCHEME 23 illustrates a schematic synthesis ofcompounds of formula (Izc). Treatment of compound of formula (2301) withan oxidant such as, but not limited to, 3-chloroperbenzoic acid in asolvent such as, but not limited to, dichloromethane provides theN-oxide product of formula (Izc).

Preparation of Compounds of Formula (Izd) and (Ize)

Compounds of formula (Izd) and (Ize) are compounds of the invention, asset forth above in the Summary of the Invention. They may be prepared bythe methods set forth below in REACTION SCHEME 24 where q, R¹⁵ and R¹⁶are as defined above:

Compounds of formula (2401) and (2402) can be prepared according tomethods known to one skilled in the art or by the methods disclosedherein or by the methods disclosed in PCT Published Patent ApplicationWO 2006/110917. Compounds (2404) and (2405) are commercially available.

In general, REACTION SCHEME 24 illustrates a schematic synthesis ofcompounds of formula (Izd) and (Ize). Treatment of compound of formula(2401) with hydrazine in a solvent such as, but not limited to,dimethoxyethane followed by reaction with isoamyl nitrite andhypophosphorous acid in a solvent such as, but not limited to, ethanolprovides the indazole product of formula (Izd).

Treatment of compound of formula (2401) with either acetohydroxamic acid

(2404) or acetone oxime (2405) in the presence of a base such as, butnot limited to, cesium carbonate in a solvent such as, but not limitedto, N,N-dimethylformamide provides the isooxazole product of formula(Ize). Alternatively, treatment of compound of formula (2402) withhydroxylamine gives the imidamide intermediate of formula (2403), whichundergoes intramolecular Mitsunobu reaction provides the isooxazoleproduct of formula (Ize).

Preparation of Compounds of Formula (Izf)

Compounds of formula (Izf) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 25 where q, R¹⁵ and R¹⁶ areas defined above:

Compounds of formula (2501) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in pct published patent application WO 2006/110917.

In general, Reaction Scheme 25 illustrates a schematic synthesis ofcompounds of formula (Izf). Treatment of compound of formula (2501) withan oxidant such as, but not limited to, 3-chloroperbenzoic acid in asolvent such as, but not limited to, dichloromethane provides thedioxide product of formula (Izf).

Preparation of Compounds of Formula (Izq)

Compounds of formula (Izg) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 26 where q, R¹⁵, R¹⁶, R²³ and

are as defined above:

Compounds of formula (2601) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in PCT Published Patent Application WO 2006/110917.Compounds of formula (2603) and formula (2607) are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein.

In general, REACTION SCHEME 26 illustrates a schematic synthesis ofcompounds of formula (Izg). Treatment of compound of formula (2601) withhydrazine gives the reduced compound of formula (2602). Treatment of(2602) with a strong base such as, but not limited to, sodium hydride ina solvent such as, but not limited to, N,N-dimethylformamide followed byreaction with a substituted 2-F-nitrobenzene gives the compound offormula (2604). Treatment of (2604) with a strong base such as, but notlimited to, lithium bis(trimethylsilyl)amide in a solvent such as, butnot limited to, tetrahydrofuran and reaction with methyl cyanoformate offormula (2605). Reduction of (2605) with hydrogen in the presence of acatalyst, palladium on carbon, in a solvent such as, but not limited to,methanol gives the cyclised product of formula (2606). Compound offormula (2606) is alkylated with the chloro or bromo compound of formula(2607) to afford the product of formula (Izg).

Preparation of Compounds of Formula (Izh)

Compounds of formula (Izh) are compounds of the invention, as set forthabove in the Summary of the Invention. They may be prepared by themethods set forth below in REACTION SCHEME 27 where q, IV, R¹⁶ and are

as defined above:

Compounds of formula (2701) can be prepared according to methods knownto one skilled in the art or by the methods disclosed herein or by themethods disclosed in pct published patent application WO 2006/110917.

In general, Reaction Scheme 27 illustrates a schematic synthesis ofcompounds of formula (Izh). Treatment of compound of formula (2701) withiodochloromethane or diiodomethane in the presence of a base such as,but not limited to, cesium carbonate in a solvent such as, but notlimited to, tetrahydrofuran or N,N-dimethylformamide provides thecyclized product of formula (Izh).

The following Preparations, which are directed to the preparation ofintermediates used in the preparation of the compounds of the invention,the following Examples, which are directed to the preparation of thecompounds of the invention, and the following Biological Examples areprovided as a guide to assist in the practice of the invention, and arenot intended as a limitation on the scope of the invention.

Preparation 1 Synthesis of1,3-bis(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) solution of 2-methylbenzo[d]thiazol-5-ol (4.0 g,24.0 mmol) in anhydrous tetrahydrofuran (50 mL) was addedisopropylmagnesium chloride (2 M solution in tetrahydrofuran, 12.0 mL,24.0 mmol). The resultant suspension was stirred at 0° C. for 0.5 h andisatin (3.1 g, 21.2 mmol) was added in one portion. The reaction mixturewas stirred at ambient temperature for 48 h and was diluted with asaturated aqueous solution of ammonium chloride (80 mL) and ethylacetate (200 mL). The phases were separated and the aqueous phase wasextracted with ethyl acetate (3×50 mL). The combined organic solutionwas washed with brine (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product was trituratedwith boiling ethyl acetate (10 mL), filtered and dried in vacuo toafford3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(4.11 g, 62%) as an off-white microcrystalline solid: ¹H NMR (300 MHz,DMSO-d₆) δ10.34 (s, 1H), 10.02 (br s, 1H), 8.85 (br s, 1H), 7.78 (d,J=8.6 Hz, 1H), 7.18-7.10 (m, 1H), 7.01-6.74 (m, 4H), 2.77 (br s, 3H); MS(ES+) m/z 313.1 (M+1).

B. Synthesis of3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one

A mixture of3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(4.81 g, 15.4 mmol) and 48% aqueous hydroiodic acid (25 mL) was heatedat reflux for 1 h. The reaction mixture was allowed to cool to ambienttemperature and was diluted with water (50 mL) and ethyl acetate (50mL). The mixture was briefly sonicated, causing a precipitate to bedeposited. The solid was collected by filtration, washed with water (20mL) and dried in vacuo to afford3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(4.52 g, 99%) as a pale yellow solid: MS (ES+) m/z 297.2 (M+1).

C. Synthesis of1,3-bis(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) suspension of3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(3.66 g, 12.4 mmol), p-formaldehyde (1.85 g, 61.8 mmol) intetrahydrofuran (30 mL) and water (30 mL) was added dropwise a solutionof sodium hydroxide (2.96 g, 74.1 mmol) in water (30 mL). The reactionmixture was stirred at 0° C. for 1.5 h, and acidified to pH 5 by thedropwise addition of 10% aqueous hydrochloric acid and was diluted withethyl acetate (50 mL). The phases were separated and the aqueous phasewas extracted with ethyl acetate (3×50 mL). The combined organicsolution was washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography with ethyl acetate in hexanes (67 to 100%gradient) to afford1,3-bis(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(1.80 g, 41%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (brs, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.23-7.15 (m, 1H), 7.11-7.06 (m, 1H),6.94-6.80 (m, 3H), 6.21-6.14 (m, 1H), 5.95 (br s, 1H), 5.26-5.18 (m,1H), 5.06-4.98 (m, 1H), 4.64-4.56 (m, 1H), 3.84-3.76 (m, 1H), 2.80 (s,3H); MS (ES+) m/z 379.0 (M+23).

Preparation 2 Synthesis of6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneA. Synthesis of3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3-bromophenol (4.4 g, 25.4 mmol) intetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (12.7mL, 2 M tetrahydrofuran solution, 25.4 mol) slowly at 0° C. The mixturewas allowed to stir for 30 min at 0° C., then the solvent was removed invacuo. Dichloromethane (100 mL) was added, followed by the addition of asolution of 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione(5.0 g, 16.9 mol) in dichloromethane (100 mL) at 0° C. The mixture wasstirred at ambient temperature for 16 h, quenched by the addition ofsaturated ammonium chloride solution. The organic layer was washed withwater, dried over sodium sulfate and concentrated in vacuo. The obtainedsolid was recrystallized from ethyl acetate/hexanes to afford3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(6.4 g, 81%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.49-5.83(m, 9H), 5.13-4.71 (m, 2H); MS (ES+) m/z 449.9 (M−17), 451.9 (M−17).

B. Synthesis of3-(4-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

A mixture of3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(5.5 g, 11.8 mmol), triethylsilane (20.0 mL, excess) and trifluoroaceticacid (20.0 mL, excess) was stirred at ambient temperature for 16 h. Themixture was concentrated under vacuum. The residue was treated withdiethyl ether to form a suspension. The filtration gave3-(4-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(4.3 g, 82%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.91 (br s,1H), 7.36 (t, J=7.9 Hz, 1H), 7.26-7.13 (m, 2H), 7.05 (d, J=7.9 Hz, 1H),6.97 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.5, 2.0 Hz, 1H), 6.73-6.67 (m, 2H),6.35 (d, J=3.5 Hz, 1H), 5.08 (s, 1H), 4.95 (s, 2H); MS (ES+) m/z 452.0(M+1), 450.0 (M+1).

C.6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of3-(4-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(4.3 g, 9.5 mmol), chloroiodomethane (1.8 mL, 25.3 mmol) intetrahydrofuran (100 mL) was added cesium carbonate (9.9 g, 30.5 mmol)under Argon. The mixture was stirred at ambient temperature for 16 h,then filtered through a pad of celite. The filtrate was concentratedunder vacuum. The residue was treated with diethyl ether/hexanes toafford6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(3.46 g, 78%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30 (td,J=7.9, 1.5 Hz, 1H), 7.16-7.03 (m, 3H), 6.69 (d, J=7.9 Hz, 1H), 6.93 (dd,J=8.2, 1.8 Hz, 1H), 6.77-6.71 (m, 1H), 6.53 (d, J=8.2 Hz, 1H), 6.42-6.37(m, 1H), 5.06 (d, J=16.1 Hz, 1H), 4.97 (d, J=9.4 Hz, 1H), 4.86 (d,J=16.1 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ176.5,161.5, 151.8, 141.4, 131.6, 129.3, 128.0, 124.5 (d), 124.0, 114.2, 112.6(d), 109.2 (d), 80.1, 57.5, 36.9; MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).

Preparation 3 Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3-methoxy-4-methylphenol (Jorgensen, E. C., etal., J. Med. Chem. (1971), 14:1199-202) (7.5 g, 54.3 mmol) indichloromethane (160 mL) was added isopropylmagnesium chloride (29.0 mL,2 M in tetrahydrofuran, 58 mmol) at 0° C. The resultant mixture wasstirred at 0° C. for 30 min followed by the addition of1-benzhydrylindoline-2,3-dione (10.4 g, 36.3 mmol). The reaction mixturewas stirred at ambient temperature for 10 min and concentrated in vacuoto dryness. The residue was dissolved in ethyl acetate (300 mL) andwashed with saturated ammonium chloride solution (2×200 mL). The ethylacetate layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to afford1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one(19.10 g) as a crude brown oil: MS (ES−) m/z 450.3 (M−1).

B. Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one

To a stirred mixture of1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one(15.4 g, 34.1 mmol) and triethylsilane (15 mL) was added trifluoroaceticacid (15 mL) at 0° C. The solution was stirred at ambient temperaturefor 16 h and concentrated in vacuo to dryness. The residue wasrecrystallized from diethyl ether (25 mL) in a Branson ultrasonic benchtop water bath to afford1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one(11.0 g, 74%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.42-7.16(m, 12H), 7.11-7.01 (m, 2H), 6.94 (s, 1H), 6.61 (s, 1H), 6.57-6.49 (m,1H), 6.45 (s, 1H), 5.08 (s, 1H), 3.63 (s, 3H), 2.03 (s, 3H); MS (ES+)m/z 436.3 (M+1).

Preparation 4 Synthesis of4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione

To a stirred solution of 4-chloroisatin (9.10 g, 50.0 mmol) inN,N-dimethylformamide (100 mL) was added sodium hydride (2.20 g, 55.0mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h,followed by the addition of bromodiphenylmethane (14.80 g, 56.8 mmol).The mixture was stirred at ambient temperature for 20 h, diluted withethyl acetate, washed with water and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was recrystallized from diethyl ether and hexanes to afford4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (14.20 g, 81%): ¹H NMR(300 MHz, CDCl₃) δ 7.37-7.17 (m, 11H), 6.98-6.95 (m, 2H), 6.42 (d, J=9.0Hz, 1H); MS (ES+) m/z 369.9 (M+23), 371.9 (M+1).

B. Synthesis of4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 3A, and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3-methoxy-4-methylphenol, and4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-benzhydrylindoline-2,3-dione,4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (87%) as a beige solid: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (brs, 1H), 7.36-7.16 (m, 10H), 7.05-7.01 (m, 2H), 6.89 (s, 1H), 6.58 (s,1H), 6.45-6.38 (m, 2H), 4.57-4.49 (m, 2H), 4.03 (br s, 1H), 3.13-2.91(m, 2H); MS (ES+) m/z 505.9 (M+1), 507.9 (M+1).

C. Synthesis of4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one(9.25 g, 19.1 mmol) in dichloromethane (25 mL) was added triethylsilane(10 mL). The mixture was cooled to 0° C. followed by the addition oftrifluoroacetic acid (10 mL) slowly over 5 min. The resultant mixturewas stirred at ambient temperature for 5 h and concentrated in vacuo todryness. The residue was triturated in diethyl ether (25 mL) in aBranson ultrasonic bench top water bath to afford4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one(8.90 g, quantitative) as a beige solid: MS (ES+) m/z 468.0 (M+1), 470.0(M+1).

Preparation 5 Synthesis of3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3-bromophenol (11.9 g, 69.2 mmol) indichloromethane (160.0 mL) at 0° C. was added isopropylmagnesiumchloride (2.0 M in tetrahydrofuran, 38.0 mL, 76.1 mmol). The solutionwas stirred at 0° C. for 30 min, then 1-benzhydrylindoline-2,3-dione(10.0 g, 34.6 mmol) was added. The reaction was stirred at ambienttemperature for 16 h, then concentrated in vacuo to dryness. The residueobtained was dissolved in ethyl acetate (400.0 mL) and washed withsaturated ammonium chloride solution (3×100.0 mL). The organic phase wasdried over magnesium sulfate, filtered and concentrated in vacuo todryness. Purification by flash chromatography with 30% ethyl acetate inhexanes afforded3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(11.7 g, 70%) as a beige solid: ¹H NMR (300 MHz, CDCl₃) δ9.09 (br s,1H), 7.47-7.16 (m, 11H), 7.12-7.00 (m, 3H), 6.92-6.84 (m, 2H), 6.72-6.66(m, 1H), 6.51-6.45 (m, 1H), 4.57 (br s, 1H); MS (ES+) m/z 484.2 (M+1),486.2 (M+1).

B. Synthesis of3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

To an ice cold stirred solution of3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(13.1 g, 27.1 mmol) in triethylsilane (25.0 mL) was addedtrifluoroacetic acid (25.0 mL). The solution was stirred at ambienttemperature for 64 h, then concentrated in vacuo to dryness.Recrystallization from diethyl ether (25.0 mL) in a Branson ultrasonicbench top water bath afforded3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(10.1 g, 79%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.17 (s,1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50(m, 1H), 5.10 (s, 1H); MS (ES−) m/z 468.2 (M−1), 470.2 (M−1).

Preparation 6 Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3,4-dimethylphenol (2.50 g, 20.5 mmol) intetrahydrofuran (100 mL) was added isopropylmagnesium chloride (10.2 mL,2.0 M tetrahydrofuran solution, 20.40 mmol) at 0° C. The mixture wasallowed to stir for 1 h at 0° C., then the solvent was removed in vacuo.Dichloromethane (200 mL) was added, followed by the addition of1-(diphenylmethyl)-1H-indole-2,3-dione (5.00 g, 15.95 mmol). The mixturewas stirred for 54 h at ambient temperature, quenched with saturatedammonium chloride solution. The organic layer was washed with water,brine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo, the residue was purified by columnchromatography to give1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one(5.10 g, 73%): ¹H NMR (300 MHz, CDCl₃) δ7.49-7.45 (m, 1H), 7.35-7.27 (m,10H), 7.08-7.04 (m, 2H), 6.93 (s, 1H), 6.81-6.75 (m, 1H), 6.52 (s, 1H),6.49-6.46 (m, 1H), 2.15 (s, 3H), 2.02 (s, 3H); MS (ES+) m/z 418.1(M−17).

B. Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-onewas obtained (93%): ¹H NMR (300 MHz, CDCl₃)

7.34-7.27 (m, 11H), 7.06-7.02 (m, 3H), 6.76 (s, 1H), 6.72 (s, 1H),6.55-6.50 (m, 1H), 5.05 (s, 1H), 2.17 (s, 3H), 2.12 (s, 3H); MS (ES+)m/z 420.2 (M+1).

Preparation 7 Synthesis of1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione

To a stirred solution of 5-fluoroisatin (6.00 g, 36.3 mmol) inN,N-dimethylformamide (50 mL) was added sodium hydride (1.60 g, 40.0mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hfollowed by the addition of bromodiphenylmethane (10.0 g, 38.0 mmol).The mixture was stirred at 60° C. for 7 h, diluted with ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness, the residuewas recrystallized from ethyl acetate and hexanes to give1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dione (6.30 g, 52%): ¹H NMR(300 MHz, CDCl₃)

7.39-7.27 (m, 11H), 7.04-6.97 (m, 2H), 6.46-6.42 (m, 1H); MS (ES+) m/z354.2 (M+23).

B. Synthesis of1-(diphenylmethyl)-5-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3,4-dimethylphenol, and 1-(diphenylmethyl)-5-fluoro-1H-indole-2,3-dioneto replace 1-(diphenylmethyl)-1H-indole-2,3-dione,1-(diphenylmethyl)-5-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (99%): ¹H NMR (300 MHz, CDCl₃) δ 8.94 (s, 1H), 7.36-7.19(m, 11H), 6.94 (s, 1H), 6.82-6.75 (m, 1H), 6.63 (s, 1H), 6.48-6.38 (m,2H), 4.53 (t, J=9.0 Hz, 2H), 4.38 (br s, 1H), 3.06-3.00 (m, 2H); MS(ES+) m/z 466.4 (M−1).

C. Synthesis of1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-5-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (94%): mp 179-181° C. (methanol); ¹H NMR (300 MHz, CDCl₃)δ7.36-7.19 (m, 11H), 7.02-6.97 (m, 2H), 6.77-6.69 (m, 2H), 6.45-6.39 (m,2H), 5.04 (s, 1H), 4.53 (t, J=9.0 Hz, 2H), 3.10-3.02 (m, 2H); MS (ES+)m/z 452.1 (M+1).

Preparation 8 Synthesis of1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 4A, and makingnon-critical variations using 6-fluoroisatin (Sadler, P. W., J. Org.Chem. (1956), 21(2):169-70) to replace 4-chloroisatin,1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dione was obtained (76%): mp167-169° C. (diethyl ether); ¹H NMR (300 MHz, DMSO-d₆)

7.41-7.27 (m, 11H), 6.77 (s, 1H), 6.30-6.26 (m, 1H), 5.82-5.80 (m, 1H);MS (ES+) m/z 354.1 (M+23).

B. Synthesis of1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3,4-dimethylphenol, and 1-(diphenylmethyl)-6-fluoro-1H-indole-2,3-dioneto replace 1-(diphenylmethyl)-1H-indole-2,3-dione,1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (84%): mp 147-149° C.; ¹H NMR (300 MHz, CDCl₃)

8.80 (s, 1H), 7.44-7.20 (m, 11H), 6.90 (s, 1H), 6.79-6.72 (m, 1H), 6.59(s, 1H), 6.45 (s, 1H), 6.20-6.17 (m, 1H); MS (ES+) m/z 450.1 (M−17).

C. Synthesis of1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (99%): mp 121-123° C. (methanol); ¹H NMR (300 MHz, CDCl₃)

7.36-7.16 (m, 11H), 6.95 (s, 1H), 6.77-6.71 (m, 1H), 6.67 (s, 1H), 6.46(s, 1H), 6.25-6.21 (m, 1H), 5.00 (s, 1H), 4.53 (t, J=9.0 Hz, 2H),3.08-3.01 (m, 2H); MS (ES+) m/z 451.9 (M+1).

Preparation 9 Synthesis of3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 3-methylbenzo[d]isoxazol-6-ol (Iranpoor,N., et al., Tetrahedron Lett. (2006), 47:8247) to replace3,4-dimethylphenol, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione toreplace 1-(diphenylmethyl)-1H-indole-2,3-dione,3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-onewas obtained (76%): mp 199-201° C. (ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆) δ 7.52 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.18-7.13 (m,1H), 7.05-7.03 (m, 1H), 6.89-6.75 (m, 5H), 4.83 (AB, 2H), 3.71 (s, 3H),2.77 (s, 3H); MS (ES+) m/z 417.0 (M+1).

B. Synthesis of3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one(3.70 g; 8.9 mmol) and triethylsilane (8.4 mL, 52.6 mmol) indichloromethane (50 mL) was added trifluoroacetic acid (7.0 mL, 90.8mmol). The reaction mixture was stirred at ambient temperature for 57 h,concentrated in vacuo to dryness. The residue was washed with diethylether-hexanes (1:2) to afford3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one(3.34 g, 93%): mp 195-197° C. (diethyl ether/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.37 (d, J=9.0 Hz, 2H), 7.19-7.14 (m, 1H), 7.03-6.81 (m, 6H),6.42 (d, J=9.0 Hz, 1H), 5.46 (s, 1H), 5.04 (Aq, 2H), 3.74 (s, 3H), 2.43(s, 3H); MS (ES+) m/z 401.0 (M+1).

Preparation 10 Synthesis of1-benzhydryl-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)indolin-2-one A.Synthesis of1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 4-fluoro-3-methoxyphenol to replace3,4-dimethylphenol,1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (95%): ¹H NMR (300 MHz, CDCl₃) δ9.50-9.00 (br, 1H),7.48-7.41 (m, 1H), 7.36-7.25 (m, 8H), 7.22-7.16 (m, 2H), 7.14-7.07 (m,2H), 6.88 (s, 1H), 6.64 (d, J=7.5 Hz, 1H), 6.56-6.46 (m, 2H), 4.43-4.00(br, 1H), 3.81 (s, 3H); MS (ES+) m/z 456.1 (M+1).

B. Synthesis of1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 3B, and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-onewas obtained (73%): ¹H NMR (300 MHz, CDCl₃) δ 9.33-8.84 (br, 1H),7.41-7.25 (m, 9H), 7.22-7.04 (m, 4H), 6.92 (s, 1H), 6.71 (d, J=7.7 Hz,1H), 6.64 (d, J=12.2 Hz, 1H), 6.56-6.49 (m, 1H), 5.09 (s, 1H), 3.84 (s,3H); MS (ES+) m/z 440.1 (M+1).

Preparation 11 Synthesis of1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 4-fluorophenol to replace3,4-dimethylphenol,1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (76%): ¹H NMR (300 MHz, CDCl₃) δ7.47-7.39 (m, 1H),7.37-7.19 (m, 10H), 7.14-7.06 (m, 2H), 6.94-6.87 (m, 3H), 6.62-6.55 (m,1H), 6.53-6.45 (m, 1H); MS (ES+) m/z 448.0 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 3B, and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-onewas obtained (78%): ¹H NMR (300 MHz, CDCl₃) δ 8.80 (s, 1H), 7.39-7.26(m, 9H), 7.22-7.16 (m, 2H), 7.15-7.05 (m, 2H), 7.05-6.97 (m, 1H),6.96-6.85 (m, 2H), 6.68-6.61 (m, 1H), 6.58-6.50 (m, 1H), 5.16 (s, 1H);MS (ES+) m/z 410.0 (M+1).

Preparation 12 Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 3-methoxyphenol to replace3,4-dimethylphenol,1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-onewas obtained (99%): MS (ES+) m/z 420.2 (M−17), 460.2 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(27.9 g, 63.8 mmol) in dichloromethane (200 mL) were addedtrifluoroacetic acid (2 mL) and triethylsilane (1.5 mL) at ambienttemperature. The reaction mixture was refluxed for 15 h. The mixture wasconcentrated in vacuo to dryness. The residue was purified by flashchromatograph using 25% ethyl acetate in hexane to afford1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(7.40 g, 27%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.40-7.18(m, 11H), 7.13-7.06 (m, 2H), 6.97 (s, 1H), 6.83 (d, J=8.4 Hz, 1H),6.67-6.64 (m, 1H), 6.57-6.52 (m, 1H), 6.41 (dd, J=8.4, 2.4 Hz, 1H), 5.11(s, 1H), 3.77 (s, 3H).

Preparation 13 Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3,4-dimethylphenol,1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (88%) as a pale yellow powder: mp 210-212° C. (water); ¹HNMR (300 MHz, DMSO-d₆) δ9.08 (br s, 1H), 7.42-7.24 (m, 11H), 6.97-6.79(m, 4H), 6.54 (br s, 1H), 6.29 (d, J=7.8 Hz, 1H), 6.17 (s, 1H),4.25-4.13 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.8, 3.0, 142.7, 138.3,137.8, 128.5, 128.4, 128.3, 128.0, 127.6, 127.4, 123.7, 121.6, 120.8,115.6, 110.8, 103.3, 74.1, 64.4, 63.8, 57.2; MS (ES+) m/z 488.2 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (quantitative) as a pale pink solid: mp 157-160° C.(diethyl ether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ9.19 (br s, 1H),7.42-7.27 (m, 10H), 6.98-6.91 (m, 3H), 6.88-6.82 (m, 1H), 6.69-6.63 (m,1H), 6.37 (d, J=7.8 Hz, 1H), 6.30 (s, 1H), 4.81 (s, 1H), 4.21-4.11 (m,4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.2, 149.2, 142.8, 142.6, 138.2,137.8, 135.8, 130.1, 128.6, 128.4, 128.3, 128.2, 127.7, 1275, 126.8,123.6, 121.7, 118.9, 117.0, 110.6, 103.8, 64.3, 63.8, 57.4, 47.4; MS(ES+) m/z 450.3 (M+1).

Preparation 14 Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) solution of chroman-7-ol (Cube, R. V., et al.,Bioorg. Med. Chem. Lett. (2005), 15(9):2389-93) (0.55 g, 3.66 mmol) intetrahydrofuran (11 mL) under nitrogen was added isopropylmagnesiumchloride (2.4 mL, 2 M in tetrahydrofuran, 4.8 mmol). The resultingsolution was stirred at 0° C. for 30 min. A suspension of1-(diphenylmethyl)indoline-2,3-dione (1.16 g, 3.70 mmol) indichloromethane (4 mL) was added. The reaction was stirred at 0° C. for10 min, then warmed to ambient temperature and stirred for 15.5 h. Thereaction was diluted with saturated ammonium chloride solution (10 mL)and the organic solvents were removed under reduced pressure. Theresidual mixture was diluted with water (50 mL) and extracted with ethylacetate (3×25 mL). The combined organic solution was washed with brine(50 mL), dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography with hexanes/ethyl acetate (7:3) to afford1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one(1.37 g, 81%) as a light yellow solid: mp 204-206° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.90 (s, 1H), 7.49 (dd, J=5.6,3.2 Hz, 1H), 7.38-7.23 (m, 10H), 7.12-7.06 (m, 2H), 6.95 (s, 1H),6.52-6.47 (m, 3H), 4.23 (s, 1H), 4.121 (dd, J=5.7, 4.5 Hz, 2H), 2.53 (t,J=6.3 Hz, 2H), 1.95-1.87 (m, 2H); MS (ES+) m/z 486.1 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (81%) as a pale yellow solid: mp 207-210° C. (hexanes): ¹HNMR (300 MHz, CDCl₃) δ8.43 (br s, 1H), 7.37-7.22 (m, 11H), 7.09-7.03 (m,2H), 6.99 (s, 1H), 6.58 (s, 1H), 6.56-6.50 (m, 1H), 6.48 (s, 1H), 5.05(s, 1H), 4.15-4.08 (m, 2H), 2.68-2.51 (m, 2H), 1.97-1.89 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ179.1, 155.4, 154.9, 143.4, 137.5, 137.4, 128.8,128.7, 128.6, 128.5, 128.1, 127.9, 127.3, 125.9, 122.9, 115.8, 114.6,112.8, 106.7, 66.5, 58.8, 47.3, 24.4, 22.6; MS (ES+) m/z 448.1 (M+1).

Preparation 15 Synthesis of1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzo-dioxepin-7-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 14A, and makingnon-critical variations using 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ol(Lange, J., et al., Heterocycles (2000), 53(1):197-204) to replacechroman-7-ol,1-(diphenylmethyl)-3-hydroxy-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzo-dioxepin-7-yl)-1,3-dihydro-2H-indol-2-onewas obtained (70%) as a pale orange solid: mp 115-118° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ9.25 (s, 1H), 7.42-7.29 (m,11H), 6.98-6.80 (m, 4H), 6.58 (s, 1H), 6.30 (d, J=7.8 Hz, 1H), 6.29 (s,1H), 4.14-3.98 (m, 4H), 2.10-2.02 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆)δ176.7, 150.9, 148.9, 143.3, 143.0, 138.2, 137.8, 132.5, 128.5, 128.4,128.3, 128.1, 127.6, 127.4, 123.7, 122.5, 121.7, 120.2, 110.8, 107.7,74.0, 70.71, 70.65, 57.3, 32.3; MS (ES+) m/z 502.1 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-1,3-dihydro-2H-indol-2-onewas obtained (91%) as an off-white powder: mp 193-195° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.65 (br s, 1H), 7.39-7.27 (m,9H), 7.23-7.20 (m, 2H), 7.13-7.04 (m, 2H), 6.96 (s, 1H), 6.73 (s, 1H),6.60 (s, 1H), 6.53-6.50 (m, 1H), 5.09 (s, 1H), 4.25-3.99 (m, 4H),2.22-2.06 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.9, 151.7, 151.6, 145.3,143.3, 137.4, 137.1, 128.9, 128.8, 128.6, 128.4, 128.2, 128.0, 126.5,126.1, 123.1, 120.2, 118.2, 112.9, 112.0, 71.0, 70.8, 58.9, 47.2, 32.3;MS (ES+) m/z 464.0 (M+1).

Preparation 16 Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) suspension of 2-methyl-1,3-benzoxazol-5-ol (Fujita,et al., Synthesis (1982):62-9) (10.3 g, 68.9 mmol) in anhydroustetrahydrofuran (150 mL) was added isopropylmagnesium chloride (34.4 mL,2.0 M solution in tetrahydrofuran, 68.9 mmol). The reaction mixture wasstirred at 0° C. for 0.5 h, and 1-benzhydrylindoline-2,3-dione (18.8 g,59.9 mmol) and anhydrous dichloromethane (150 mL) were added. Thereaction mixture was heated at reflux for 6 days and was allowed to coolto ambient temperature. The reaction mixture was diluted with asaturated aqueous solution of ammonium chloride (200 mL) and ethylacetate (200 mL) and the phases were separated. The aqueous phase wasextracted with ethyl acetate (2×200 mL) and the combined organicsolution was washed with brine (2×200 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by column chromatography with hexanes/ethyl acetate (3/1),followed by recrystallization from hexanes/ethyl acetate to afford1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one(3.10 g, 10%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ8.41 (brs, 1H), 7.63-7.60 (m, 2H), 7.47-7.32 (m, 10H), 7.15 (s, 1H), 7.04-6.96(m, 1H), 6.96-6.88 (m, 1H), 6.87 (d, J=9.0 Hz, 1H), 6.41 (d, 7.8 Hz,1H), 4.58 (br s, 1H), 2.44 (s, 3H); MS (ES+) m/z 445.2 (M−17).

B. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1B, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-oneto replace3-hydroxy-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (87%) as a colorless solid: MS (ES+) m/z 447.4 (M+1).

Preparation 17 Synthesis of7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-oneA. Synthesis of7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Following the procedure as described in PREPARATION 14A, and makingnon-critical variations using6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (Loudon and Ogg, J.Chem. Soc., 1955:739-743) to replace chroman-7-ol,7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-onewas obtained (27%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆)δ9.44 (s, 1H), 7.46-7.25 (m, 11H), 7.01-6.77 (m, 4H), 6.68 (s, 1H), 6.43(s, 1H), 6.38-6.27 (m, 1H), 4.60 (s, 2H), 3.19 (s, 3H); MS (ES−) m/z491.5 (M−1).

B. Synthesis of7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one

To a solution of7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one(4.0 g, 8.1 mmol) in trifluoroacetic acid (1.8 mL, 24.4 mmol) was addedtriethylsilane (3.9 mL, 24.4 mmol) and the reaction mixture was stirredat ambient temperature for 16 h. The reaction mixture was concentratedin vacuo and the crude product was purified by column chromatographywith ethyl acetate in hexanes (10 to 100% gradient) to afford7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one(2.66 g, 71%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.53 (s,1H), 7.44-7.28 (m, 10H), 6.99-6.95 (m, 3H), 6.89-6.84 (m, 2H), 6.54 (s,1H), 6.40 (m, 1H), 4.90 (s, 1H), 4.57 (s, 2H), 3.21 (s, 3H); MS (ES+)m/z 477.0 (M+1).

Preparation 18 Synthesis of6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-oneA. Synthesis of 7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one

To a cooled (0° C.) solution of7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one (10.0 g, 56 mmol) in water(80 mL) was added concentrated sulfuric acid (17 mL). After stirring at0° C. for 10 min, a solution of sodium nitrite (4.1 g, 59 mmol) in water(10 mL) was added dropwise. After stirring for 0.5 h, the reactionmixture was added dropwise to a solution of cupric sulfate (50 g) inwater (300 mL) at reflux. Once the addition was complete, the reactionmixture was allowed to cool to ambient temperature and was extractedwith ethyl acetate (5×200 mL). The combined organic solution was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by trituration with ice-cold ethyl acetate (25 mL)and the solid was collected by vacuum filtration, air-dried and driedunder high vacuum to afford7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one (3.22 g, 32%) as a tansolid: ¹H NMR (300 MHz, DMSO-d₆) δ9.40 (s, 1H), 6.95 (d, J=8.7 Hz, 1H),6.45 (dd, J=8.7, 2.6 Hz, 1H), 6.40 (d, J=2.6 Hz, 1H), 4.56 (s, 2H), 3.21(s, 3H); MS (ES+) m/z 180.1 (M+1).

B. Synthesis of6-[1′-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Following the procedure as described in PREPARATION 16A, and makingnon-critical variations using7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one to replace2-methyl-1,3-benzoxazol-5-ol,6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-onewas obtained (74%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆)δ9.54 (s, 1H), 7.55 (s, 1H), 7.42-7.30 (m, 10H), 6.99-6.94 (m, 2H), 6.88(s, 1H), 6.86-6.80 (m, 1H), 6.71 (s, 1H), 6.35-6.30 (m, 2H), 4.61 (s,2H), 3.32 (s, 3H); MS (ES+) tri/z 475.0 (M−17).

C. Synthesis of6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one

Following the procedure as described in PREPARATION 17B, and makingnon-critical variations using6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-oneto replace7-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)-6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one,6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-onewas obtained (65%) as an amorphous solid: MS (ES+) m/z 477.4 (M+1).

Preparation 19 Synthesis of6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneA. Synthesis of5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one

To a solution of 5-hydroxy-1,3-benzoxazol-2(3H)-one (Itoh, et al., J.Org. Chem. 2002 (67):7424-7428) (1.00 g, 6.6 mmol) in anhydrousN,N-dimethylformamide (10 mL) was added imidazole (0.54 g, 7.9 mmol),followed by chloro-tert-butyldimethylsilane (1.10 g, 7.3 mmol). Thereaction mixture was stirred at ambient temperature for 16 h andconcentrated in vacuo. The crude product was purified by columnchromatography with ethyl acetate in hexanes (0 to 50% gradient) toafford 5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.53g, 87%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.04 (br s, 1H),7.04 (d, J=8.3 Hz, 1H), 6.60-6.53 (m, 2H), 0.98 (s, 9H), 0.19 (s, 6H).

B. Synthesis of5-{[tert-butyl(dimethyl)sily])oxy}-3-methyl-1,3-benzoxazol-2(3H)-one

To a cooled (0° C.) solution of5-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzoxazol-2(3H)-one (1.45 g, 5.4mmol) in anhydrous N,N-dimethylformamide (10 mL) was added sodiumhydride (0.26 g, 60% dispersion in mineral oil, 6.6 mmol). The reactionmixture was stirred at 0° C. for 15 min followed by the addition ofiodomethane (1.0 mL, 16 mmol). The reaction mixture was stirred atambient temperature for 16 h and diluted with water (20 mL) and ethylacetate (20 mL). The phases were separated and the aqueous phase wasextracted with ethyl acetate (2×20 mL). The combined organic solutionwas washed with water (5×20 mL) and brine (2×20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with ethyl acetate inhexanes (0 to 25% gradient) to afford5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one(1.26 g, 83%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.02 (d,J=8.6 Hz, 1H), 6.55 (dd, J=8.6, 2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H),3.35 (s, 3H), 0.99 (s, 9H), 0.20 (s, 6H).

C. Synthesis of 5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

To a cooled (0° C.) solution of5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one(1.20 g, 4.3 mmol) in anhydrous tetrahydrofuran (15 mL) was addeddropwise tetra-n-butylammonium fluoride (4.7 mL, 1 M in tetrahydrofuran,4.7 mmol). The reaction mixture was stirred at ambient temperature for16 h and concentrated in vacuo. To the residue was added ethyl acetate(10 mL) and a 1 M solution of hydrochloric acid (20 mL) and theresultant suspension was sonicated for 5 min. The product was collectedby vacuum filtration, washed with ethyl acetate (10 mL), air-dried anddried under high vacuum to afford5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one (0.47 g, 67%) as a pinksolid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.52 (br s, 1H), 7.09 (d, J=8.6 Hz,1H), 6.62 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.6, 2.4 Hz, 1H), 3.27 (s, 3H);MS (ES−) m/z 164.2 (M−1).

D. Synthesis of6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

Following the procedure as described in PREPARATION 16A, and makingnon-critical variations using5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace2-methyl-1,3-benzoxazol-5-ol,6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (66%) as a pinksolid: MS (ES+) m/z 461.1 (M−17).

E. Synthesis of6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

Following the procedure as described in PREPARATION 9B, and makingnon-critical variations using6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneto replace3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one,6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-onewas obtained (98%) as a yellow amorphous solid: MS (ES+) m/z 463.4(M+1).

Preparation 20 Synthesis of5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneA. Synthesis of6-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one

To a solution of 6-hydroxy-1,3-benzoxazol-2(3H)-one (4.9 g, 32 mmol) inanhydrous N,N-dimethylformamide (40 mL) was added imidazole (2.6 g, 39mmol) and chloro-tert-butyldimethylsilane (5.4 g, 35 mmol). The reactionmixture was stirred at ambient temperature for 16 h and diluted withethyl acetate (100 mL). The resultant suspension was filtered and thefiltrate was concentrated in vacuo. The residue was taken up inanhydrous N,N-dimethylformamide (50 mL) and cooled to 0° C. To thissolution was added sodium hydride (1.6 g, 60% dispersion in mineral oil,39 mmol) and the reaction mixture was stirred at 0° C. for 15 min.Iodomethane (6.1 mL, 97 mmol) was added and the reaction mixture wasstirred at ambient temperature for 16 h. The reaction mixture wasconcentrated in vacuo and the residue was taken up in water (100 mL) andethyl acetate (100 mL). The phases were separated and the aqueous phasewas extracted with ethyl acetate (2×100 mL). The combined organicsolution was washed with water (2×100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/ethyl acetate(5/1) to afford6-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one(6.55 g, 72%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ6.79-6.72(m, 2H), 6.69-6.64 (m, 1H), 3.36 (s, 3H), 0.98 (s, 9H), 0.17 (s, 6H).

B. Synthesis of 6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

Following the procedure as described in PREPARATION 19C, and makingnon-critical variations using6-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one toreplace5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one,6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (99%) as a tansolid: ¹H NMR (300 MHz, DMSO-d₆) δ9.50 (br s, 1H), 7.02 (d, J=8.4 Hz,1H), 6.75 (d, J=2.1 Hz, 1H), 6.62 (dd, J=8.4, 2.1 Hz, 1H), 3.27 (s, 3H);MS (ES−) m/z 164.2 (M−1).

C. Synthesis of5-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

Following the procedure as described in PREPARATION 15A, and makingnon-critical variations using6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace2-methyl-1,3-benzoxazol-5-ol,5-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (46%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ9.62 (br s, 1H), 7.64 (s, 1H),7.47-7.25 (m, 10H), 7.06-6.71 (m, 5H), 6.65 (s, 1H), 6.30 (d, J=7.9 Hz,1H), 3.38 (s, 3H); MS (ES+) m/z 479.1 (M+1).

D. Synthesis of5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one

Following the procedure as described in PREPARATION 17B, and makingnon-critical variations using5-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneto replace7-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)-6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one,5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-onewas obtained (73%) as a pale pink solid: MS (ES+) m/z 463.4 (M+1).

Preparation 21 Synthesis of7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 4A, and makingnon-critical variations using 7-chloro-1H-indole-2,3-dione to replace4-chloro-1H-indole-2,3-dione,7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (38%) as anorange solid: mp 172-173° C. (hexanes/ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆) δ 7.71-7.60 (m, 2H), 7.36-7.27 (m, 11H), 7.22-7.17 (m, 1H).

B. Synthesis of7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) solution of 2,3-dihydrobenzofuran-6-ol (0.52 g, 3.8mmol) in anhydrous tetrahydrofuran (25 mL) was added isopropylmagnesiumchloride (2.1 mL, 2 M solution in tetrahydrofuran, 4.2 mmol). Theresultant suspension was stirred at 0° C. for 0.5 h and followed by theaddition of 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (2.11 g,15.5 mmol) in one portion. The reaction mixture was stirred at ambienttemperature for 3 h and concentrated in vacuo. The crude product waspurified by column chromatography with ethyl acetate in hexanes (0% to50% gradient) to afford7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one(7.12 g, 95%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.43 (s,1H), 7.56-7.18 (m, 13H), 6.99-6.86 (m, 2H), 6.60 (s, 1H), 6.08 (s, 1H),4.56 (t, J=8.6 Hz, 2H), 3.10 (t, J=8.6 Hz, 2H).

C. Synthesis of7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using7-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (64%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.53(s, 1H), 7.44-7.20 (m, 13H), 7.01-6.91 (m, 2H), 6.22 (s, 1H), 4.82 (s,1H), 4.48 (t, J=8.5 Hz, 2H), 3.03 (t, J=8.5 Hz, 2H).

Preparation 22 Synthesis of1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 4A, and makingnon-critical variations using 7-fluoro-1H-indole-2,3-dione (Kalia, N.,et al., J. Med. Chem. 2007; 50:21-39) to replace4-chloro-1H-indole-2,3-dione,1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione was obtained (56%) as anorange solid: ¹H NMR (300 MHz, CDCl₃) δ7.52-7.47 (m, 1H), 7.42-7.30 (m,10H), 7.29-7.21 (m, 1H), 7.13-7.05 (m, 1H), 6.99 (br s, 1H); MS (ES+)m/z 353.9 (M+23).

B. Synthesis of1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 21B, makingnon-critical variations using1-(diphenylmethyl)-7-fluoro-1H-indole-2,3-dione to replace7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione,1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-onewas obtained (99%) as a colorless solid: mp 121-122° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, DMSO-d₆) δ9.44 (s, 1H), 7.62 (s, 1H),7.42-7.29 m, 10H), 6.98 (s, 1H), 6.93-6.87 (m, 2H), 6.78-6.65 (m, 2H),6.11 (s, 1H), 4.52 (t, J=8.7 Hz, 2H), 3.14 (t, J=8.6 Hz, 2H); MS (ES+)m/z 467.9 (M+1).

Preparation 23 Synthesis of1-(diphenylmethyl)-4-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-4-fluoro-7-methyl-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 4A, and makingnon-critical variations using 4-fluoro-7-methyl-1H-indole-2,3-dione(Cassebaum, J. Prakt. Chem. (1960) 12:91-92) to replace4-chloro-1H-indole-2,3-dione,1-(diphenylmethyl)-4-fluoro-7-methyl-1H-indole-2,3-dione was obtained(45%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ7.38-7.27 (m, 11H),6.81 (s, 1H), 6.71 (dd, J=8.3, 8.3 Hz, 1H), 2.27 (s, 3H); MS (ES+) m/z367.7 (M+23).

B. Synthesis of1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 21B, and makingnon-critical variations using1-(diphenylmethyl)-4-fluoro-7-methyl-1H-indole-2,3-dione to replace1-(diphenylmethyl)-7-chloro-1H-indole-2,3-dione,1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-onewas obtained (56%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.88(s, 1H), 7.40-7.09 (m, 11H), 6.85-6.79 (m, 2H), 6.60 (br s, 1H), 6.38(s, 1H), 4.54 (m, 2H), 4.08 (s, 1H), 3.13-2.94 (m, 2H), 2.28 (br s, 3H);MS (ES+) m/z 503.8 (M+23).

C. Synthesis of1-(diphenylmethyl)-4-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-4-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-7-methyl-1,3-dihydro-2H-indol-2-onewas obtained (61%) as a colorless solid: MS (ES+) m/z 465.7 (M+1).

Preparation 24 Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 4-bromophenol to replace3,4-dimethylphenol, and1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione to replace1-(diphenylmethyl)-1H-indole-2,3-dione,3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-onewas obtained (62%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s,1H), 7.49-7.37 (m, 2H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.25-7.17 (m, 1H),7.03 (d, J=7.9 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H),6.74-6.68 (m, 1H), 6.38-6.32 (m, 1H), 5.00-4.81 (m, 2H), 4.09 (s, 1H);MS (ES+) m/z 449.9 (M−17), 451.3 (M−17).

B. Synthesis of3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 17B, and makingnon-critical variations using3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-oneto replace7-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one,3-(5-bromo-2-hydroxyphenyl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (89%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.78(br s, 1H), 7.44-7.36 (m, 1H), 7.36-7.19 (m, 3H), 7.08 (d, J=7.9 Hz,1H), 6.99 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.73-6.68 (m, 1H),6.37-6.32 (m, 1H), 5.10 (s, 1H), 5.00-4.85 (m, 2H); MS (ES+) m/z 452.0(M+1).

Preparation 25 Synthesis of8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-oneA. Synthesis of6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione

To a stirred solution of 6H-thiazolo[5,4-e]indole-7,8-dione (2.83 g,13.9 mmol) in a mixture of anhydrous tetrahydrofuran (120 mL) andN,N-dimethylformamide (80 mL) was added cesium carbonate (23.0 g, 70mmol) at ambient temperature. The deep purple mixture was stirred for0.5 h followed by the addition of 1-bromo-3-methylbutane (4.15 mL, 35.0mmol) in one portion. The mixture was stirred at ambient temperature for16 h and poured into 800 mL of ice-water and extracted with ethylacetate. The orange solution was filtered through Celite, dried overmagnesium sulfate and filtered.

The filtrate was concentrated in vacuo to dryness and the residue wastriturated with diethyl ether to afford6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (2.2 g, 57%):¹H NMR (300 MHz, CDCl₃) δ9.36 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.37 (d,J=8.6 Hz, 1H), 3.77-3.69 (m, 2H), 1.74-1.58 (m, 1H), 1.57-1.47 (m, 2H),0.94 (d, J=6.5 Hz, 6H).

B. Synthesis of8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3,4-dimethylphenol, and6-(3-methylbutyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione to replace1-(diphenylmethyl)-1H-indole-2,3-dione,8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-onewas obtained (46%): ¹H NMR (300 MHz, CDCl₃) δ9.00 (s, 1H), 8.80 (s, 1H),7.96 (d, J=8.5 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.55 (s,1H), 4.15 (s, 4H), 3.81-3.59 (m, 2H), 1.79-1.55 (m, 1H), 1.56-1.42 (m,2H), 0.93 (d, J=6.6 Hz, 6H); MS (ES+) m/z 427.0 (M+1).

C. Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one

Following the procedure as described in PREPARATION 12B, and makingnon-critical variations using8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-oneto replace1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one,8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(3-methylbutyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-onewas obtained (93%): MS (ES+) m/z 411.0 (M+1).

Preparation 26 Synthesis of8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneA. Synthesis of6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione

To a stirred solution of2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey andSternbach, Synthesis 1993:993-997) (3.08 g, 15.0 mmol) in dryN,N-dimethylformamide (150 mL) was added sodium hydride (0.9 g, 60% inmineral oil, 22.5 mmol) at ambient temperature. The deep purple mixturewas stirred for 20 min followed by the addition of2-(bromomethyl)-5-(trifluoromethyl)furan (3.80 g, 16.5 mmol) in oneportion. The dark solution was stirred at ambient temperature for 1 hand concentrated in vacuo to dryness. The residue was mixed with water(150 mL) and stirred. The fine orange precipitation was filtered off anddried to afford6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione(4.13 g, 78%): ¹H NMR (300 MHz, CDCl₃) δ7.18 (s, 1H), 6.76-6.73 (m, 1H),6.48 (s, 1H), 6.45-6.40 (m, 1H), 4.85 (s, 2H), 4.42-4.32 (m, 2H),4.28-4.20 (m, 2H).

B. Synthesis of8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3,4-dimethylphenol, and6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dioneto replace 1-(diphenylmethyl)-1H-indole-2,3-dione,8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-onewas obtained (76%): ¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 7.07 (s,1H), 6.74-6.68 (m, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H),6.36-6.32 (m, 1H), 4.84 (dd, J=48.7, 16.3 Hz, 2H), 4.53 (t, J=8.7 Hz,2H), 4.32-4.20 (m, 4H), 4.16 (s, 1H), 3.08-2.94 (m, 2H); MS (ES+) m/z471.9 (M−17).

C. Synthesis of8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

To a solution of8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one(1.81 g, 3.70 mmol) in dichloromethane (50 mL) were added triethylsilane(6.0 mL) and trifluoroacetic acid (10 mL) at 0° C. The resultant mixturewas stirred at 0° C. for 2 h and concentrated in vacuo to dryness toafford8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one(1.70 g, 97%): MS (ES+) m/z 473.9 (M+1).

Preparation 27 Synthesis of8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneA. Synthesis of6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione

To a stirred solution of 2H-[1,4]dioxino[2,3-f]indole-7,8(3H,6H)-dione(2.05 g, 10.0 mmol) in dry N,N-dimethylformamide (100 mL) was addedcesium carbonate (4.4 g, 12.0 mmol) at ambient temperature. The darkmixture was stirred for 1 h, followed by the addition of(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (3.07 g, 12.0mmol) in one portion and potassium iodide (0.66 g, 4.0 mmol). The darkmixture was stirred at 70° C. for 16 h. The mixture was poured into 5%hydrochloric acid solution (300 mL) and extracted with ethyl acetate.The organic layer was separated, dried over magnesium sulfate, filteredand evaporated. The residue was purified by flash column chromatographywith ethyl acetate in hexanes (30 to 50% gradient) to afford6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione(0.59 g, 20%): MS (ES+) m/z 290.2 (M+1).

B. Synthesis of8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3,4-dimethylphenol, and6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dioneto replace 1-(diphenylmethyl)-1H-indole-2,3-dione,8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained: R_(f) 0.45 (ethyl acetate/hexanes, 1/1); MS (ES+) m/z408.1 (M−17).

C. Synthesis of8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 12B, and makingnon-critical variations using8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneto replace1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one,8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained (76%): ¹H NMR (300 MHz, CDCl₃) δ9.27-9.07 (m, 1H),6.90-6.81 (m, 1H), 6.74 (s, 1H), 6.72-6.68 (m, 1H), 6.53 (s, 1H),4.99-4.89 (m, 1H), 4.62-4.45 (m, 2H), 4.38-4.08 (m, 5H), 3.94-3.57 (m,4H), 3.18-2.89 (m, 2H), 2.06-1.93 (m, 1H), 1.93-1.78 (m, 2H), 1.72-1.55(m, 1H); MS (ES+) m/z 410.0 (M+1).

Preparation 28 Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneA. Synthesis of8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3,4-dimethylphenol, and6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dioneto replace 1-(diphenylmethyl)-1H-indole-2,3-dione,8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-onewas obtained (80%): ¹H NMR (300 MHz, CDCl₃) δ8.78 (s, 1H), 7.07-6.97 (m,1H), 6.71-6.65 (m, 1H), 6.60-6.55 (m, 1H), 6.51-6.47 (m, 1H), 6.40-6.35(m, 1H), 6.31-6.25 (m, 1H), 4.89-4.69 (m, 2H), 4.34-4.04 (m, 9H); MS(ES+) m/z 487.9 (M−17).

B. Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 26C, and makingnon-critical variations using8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneto replace8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one,8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained (89%): ¹H NMR (300 MHz, CDCl₃) δ8.46 (s, 1H), 6.86 (s, 1H),6.69 (d, J=2.9 Hz, 1H), 6.61 (s, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 6.29(d, J=2.9 Hz, 1H), 4.95 (s, 1H), 4.89-4.74 (m, 2H), 4.31-4.06 (m, 8H).

Preparation 29 Synthesis of3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onetrifluoroacetate salt A. Synthesis of4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol

To a −78° C. solution of 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazine(90%, 10.40 g, 41.0 mmol) in tetrahydrofuran (70 mL) under nitrogen wasslowly added n-butyllithium solution (1.4 M in hexanes, 32 mL, 45 mmol)and the resulting suspension was stirred at −78° C. for 35 min.Trimethyl borate (6.0 mL, 54 mmol) was then added dropwise and the clearsolution was stirred at −78° C. for 25 min and at ambient temperaturefor 16 h. The reaction was cooled to 0° C. and aqueous hydrogen peroxide(8.2 mL, 35%, 95 mmol) was slowly added. The resulting mixture wasstirred at 0° C. for 10 min and at ambient temperature for 5 h. Theinsoluble material was removed by filtration and the filter cake waswashed with ethyl acetate. The filtrate was concentrated under reducedpressure and the residue was taken up into ethyl acetate (100 mL) andwas acidified with hydrochloric acid (100 mL, 1 M). The layers wereseparated and the organic solution was extracted with water (2×50 mL).The combined aqueous solution was neutralized to pH ˜6-7 with 5 M sodiumhydroxide and extracted with ethyl acetate (3×100 mL). This organicsolution was washed with brine (200 mL) and dried over sodium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash column chromatography with hexanes/ethylacetate (2:1) to afford 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol(6.04 g, 89%) as a light brown solid: mp 84-87° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃) δ6.59 (d, J=9.0 Hz, 1H), 6.40-6.28 (m, 2H), 5.42(br s, 1H), 4.30 (dd, J=4.2, 4.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.80 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ149.1, 145.6, 130.5, 114.7, 108.0, 104.1,65.3, 49.8, 40.1; MS (ES+) m/z 166.1 (M+1).

B. Synthesis of3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 21B, and makingnon-critical variations using4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace2,3-dihydrobenzofuran-6-ol, and1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione to replace7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione,3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (56%) as a colourless powder: mp 184-186° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (s, 1H), 7.24-7.18 (m,2H), 7.13 (s, 1H), 7.00-6.90 (m, 3H), 6.59 (d, J=3.3 Hz, 1H), 6.50 (s,1H), 6.03 (s, 1H), 4.99 (s, 2H), 4.20 (t, J=4.1 Hz, 2H), 3.14-3.09 (m,2H), 2.80 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 153.8, 145.8,144.1, 142.8, 139.3 (q, J=42 Hz), 132.7, 128.9, 128.5, 123.7, 122.2,119.6, 119.1 (q, J=266 Hz), 114.1, 112.3, 109.1, 108.3, 103.1, 74.7,64.9, 49.2, 39.4, 36.4; MS (ES+) m/z 461.2 (M+1).

C. Synthesis of3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onetrifluoroacetate salt

To a cooled (0° C.) solution of triethylsilane (1.1 mL, 6.9 mmol) intrifluoroacetic acid (6.5 mL) was slowly added3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(1.00 g, 2.18 mmol) portionwise as a solid. The resulting brown solutionwas warmed to reflux and stirred under nitrogen for 2 h. The reactionwas cooled and the solvent was removed under reduced pressure. Theresidue was precipitated from ethyl acetate/hexanes and collected byfiltration to afford3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onetrifluoroacetate salt (1.09 g, 90%) as a light grey powder: mp 143-148°C. (hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ8.98 (br s, 2H), 7.24-7.15 (m,2H), 7.05-6.92 (m, 3H), 6.62 (s, 1H), 6.61 (s, 1H), 6.22 (s, 1H), 5.08(d, J=16.7 Hz, 1H), 5.01 (d, J=16.7 Hz, 1H), 4.78 (s, 1H), 4.27-4.21 (m,2H), 3.23-3.17 (m, 2H), 2.77 (s, 3H); MS (ES+) m/z 445.2 (M+1).

Preparation 30 Synthesis of3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate A. Synthesis of1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 4A, and makingnon-critical variations using isatin to replace 4-chloroisatin, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replacebromodiphenylmethane,1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione was obtained(47%) as a thick red oil: ¹H NMR (300 MHz, CDCl₃) δ7.60-7.54 (m, 2H),7.14-7.07 (m, 2H), 4.25-4.17 (m, 1H), 3.92-3.82 (m, 2H), 3.78-3.69 (m,2H), 2.13-2.02 (m, 1H), 1.98-1.85 (m, 2H), 1.74-1.65 (m, 1H); ¹³C NMR(75 MHz, CDCl₃) δ183.5, 158.8, 151.8, 138.5, 125.3, 123.8, 117.7, 111.7,68.4, 44.7, 29.3, 25.8; MS (ES+) m/z 232.1 (M+1).

B. Synthesis of3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 13A, and makingnon-critical variations using4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replacechroman-7-ol, and1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace1-(diphenylmethyl)indoline-2,3-dione,3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onewas obtained (91%) as a pale grey solid: ¹H NMR (300 MHz, CDCl₃)(diastereomers) δ 8.94 (s, 0.4H), 8.80 (s, 0.6H), 7.52-7.48 (m, 1H),7.41-7.34 (m, 1H), 7.20-7.08 (m, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 4.51(s, 0.4H), 4.44 (s, 0.6H), 4.29-4.17 (m, 3H), 3.90-3.64 (m, 4H),3.17-2.99 (m, 2H), 2.58 (s, 3H), 2.04-1.78 (m, 3H), 1.74-1.60 (m, 1H);¹³C NMR (diastereomers) (75 MHz, CDCl₃) δ179.4, 179.2, 149.4, 149.3,146.2, 143.2, 143.0, 130.2, 130.1, 129.8, 129.6, 125.9, 125.7, 123.6,123.5, 117.6, 112.7, 112.4, 110.4, 110.3, 107.4, 79.3, 79.2, 76.9, 76.7,68.3, 68.2, 65.3, 49.5, 44.7, 44.6, 39.5, 29.3, 29.1, 25.7, 25.6; MS(ES+) m/z 419.1 (M+23).

C. Synthesis of3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate

Following the procedure as described in PREPARATION 12B, and makingnon-critical variations using3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one,3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate was obtained (93%) as a pink solid: ¹H NMR (300 MHz,DMSO-d₆) (diastereomers) δ9.07 (br s, 1H), 7.24-7.17 (m, 1H), 7.12-7.05(m, 1H), 7.01-6.88 (m, 2H), 6.63, 6.57 (s, 1H), 6.24, 6.21 (s, 1H),4.71, 4.68 (s, 1H), 4.32-4.11 (m, 3H), 3.85-3.58 (m, 4H), 3.25-3.14 (m,2H), 2.79, 2.75 (s, 3H), 1.98-1.61 (m, 4H); MS (ES+) m/z 381.1 (M+1).

Preparation 31 Synthesis of3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 14A, and makingnon-critical variations using4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ol (McMurtrey, K. D., etal., J. Org. Chem. (1970), 35(12):4252-3) to replace chroman-7-ol, and1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace1-(diphenylmethyl)indoline-2,3-dione,3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onewas obtained (92%) as a pale brown solid: ¹H NMR (300 MHz, CDCl₃) δ9.21(d, J=13.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.36 (dd, J=7.8, 7.8 Hz,1H), 7.17 (dd, J=7.5, 7.2 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 6.40 (s, 1H),6.18 (s, 1H), 4.25-4.06 (m, 3H), 3.87-3.63 (m, 4H), 3.27-3.17 (m, 2H),2.87 (s, 3H), 2.02-1.74 (m, 3H), 1.71-1.57 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ179.8, 179.7, 151.54, 151.52, 143.1, 143.0, 138.0, 137.4,130.12, 130.10, 129.32, 129.29, 126.1, 126.0, 123.8, 114.8, 114.6,113.1, 113.0, 110.4, 110.3, 103.5, 79.11, 79.06, 76.9, 76.7, 68.32,68.26, 64.6, 48.9, 44.6, 38.5, 29.3, 29.1, 25.7, 25.6; MS (ES+) m/z418.9 (M+23).

B. Synthesis of3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) solution of triethylsilane (1.3 mL, 8.2 mmol) intrifluoroacetic acid (8 mL) was added dropwise a solution of3-hydroxy-3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one(1.04 g, 2.62 mmol) in dichloromethane (3 mL). The resulting solutionwas warmed to reflux and stirred under nitrogen for 90 min. Once cooled,the solvent was removed under reduced pressure to afford3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate as a light brown foam: MS (ES+) m/z 381.0 (M+1).

Preparation 32 Synthesis of3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 6A, and makingnon-critical variations using 4H-benzo[d][1,3]dioxin-7-ol to replace3,4-dimethylphenol, and(R)-1-((tetrahydrofuran-2-yl)methyl)indoline-2,3-dione to replace1-(diphenylmethyl)-1H-indole-2,3-dione,3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onewas obtained (62%) as a colorless solid: MS (ES+) m/z 366.2 (M−17).

B. Synthesis of3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 9B, and makingnon-critical variations using3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-oneto replace3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one,3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onewas obtained (84%) as a colorless solid: MS (ES+) m/z 368.2 (M+1).

Preparation 33 Synthesis of (S)-2-(benzyloxymethoxy)propyl4-methylbenzenesulfonate

To a stirred solution of (2S)-2-[(benzyloxy)methoxy]propan-1-ol (Banfi,L., et al., J. Org. Chem. (1984), 49:3784-90) (11.40 g, 0.058 mol) indichloromethane (50 mL) and pyridine (20 mL) was added p-toluenesulfonylchloride (11.0 g, 0.057 mol) at 0° C. The reaction mixture was stirredat ambient temperature for 20 h, diluted with ethyl acetate and washedwith water, 5% hydrochloric acid solution, water and brine; dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo. The residue was purified by column chromatography to afford(S)-2-(benzyloxymethoxy)propyl 4-methylbenzenesulfonate (17.10 g, 84%):¹H NMR (300 MHz, CDCl₃)

7.77 (d, J=8.3 Hz, 2H), 7.36-7.25 (m, 7H), 4.71 (s, 2H), 4.59-4.48 (m,2H), 4.02-3.93 (m, 3H), 2.41 (s, 3H), 1.19-1.11 (m, 3H).

Preparation 34 Synthesis of 2-(bromomethyl)-7-fluorobenzofuran A.Synthesis of ethyl 7-fluorobenzofuran-2-carboxylate

A mixture of 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol),potassium carbonate (9.85 g, 71.4 mmol), and ethyl bromoacetate (4.30ml, 39.3 mmol) in N,N-dimethylformamide (70 mL) was heated at 100° C.for 16 h. The mixture was diluted with water (500 mL) and extracted withethyl acetate (3×150 mL). The combined organic solution was washed withbrine (150 mL), dried over anhydrous magnesium sulfate, filtered,concentrated in vacuo. The residue was purified by column chromatography(hexanes/ethyl acetate, 49/1→9/1) to afford ethyl7-fluorobenzofuran-2-carboxylate (3.86 g, 52%) as a yellowish oil: ¹HNMR (300 MHz, CDCl₃) δ7.56-7.54 (m, 1H), 7.47-7.42 (m, 1H), 7.28-7.14(m, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).

B. Synthesis of (7-fluorobenzofuran-2-yl)methanol

To a stirred solution of ethyl 7-fluorobenzofuran-2-carboxylate (3.70 g,17.8 mmol) in tetrahydrofuran (70 mL) was added lithium aluminum hydride(6.7 mL, 2.0 M solution in tetrahydrofuran, 13.3 mmol) at 0° C. Themixture was stirred at 0° C. for 0.5 h and solid sodium sulfatedecahydrate (15.0 g) was added slowly in portions. The mixture wasstirred at 0° C. for 10 min and at ambient temperature for 30 min. Thesolid was filtered off and washed with ethyl acetate (3×150 mL). Thecombined filtrate was washed with brine (150 mL), dried over anhydrousmagnesium sulfate, filtered, concentrated in vacuo. The residue waspurified by column chromatography (hexanes/ethyl acetate, 7/1→4/1) toafford (7-fluorobenzofuran-2-yl)methanol (2.4 g, 81%) as a colorlesssolid: ¹H NMR (300 MHz, CDCl₃) δ7.34-7.29 (m, 1H), 7.19-7.10 (m, 1H),7.06-6.98 (m, 1H), 6.73-6.69 (m, 1H), 4.82-4.78 (m, 2H), 2.07-2.01 (m,1H); MS (ES+) m/z 167.1 (M+1).

C. Synthesis of 2-(bromomethyl)-7-fluorobenzofuran

A mixture of (7-fluorobenzofuran-2-yl)methanol (1.38 g, 8.31 mmol),tetrabromomethane (4.41 g, 13.3 mmol) and triphenylphosphine (2.61 g,9.97 mmol) in dichloromethane (42 mL) was stirred at 0° C. for 2 h andconcentrated in vacuo to dryness. The residue was purified by columnchromatography (hexanes/ethyl acetate, 49/1) to afford2-(bromomethyl)-7-fluorobenzofuran (1.85 g, 97%) as a colorless solid:¹H NMR (300 MHz, CDCl₃) 7.34-7.29 (m, 1H), 7.20-7.12 (m, 1H), 7.10-7.02(m, 1H), 6.82-6.77 (m, 1H), 4.60 (s, 2H).

Preparation 35 Synthesis of (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate

To a cooled (0° C.) solution of (S)-(1,4-dioxan-2-yl)methanol (Kim, H.Y., et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) (2.02 g, 17.1mmol) and pyridine (14 mL, 173 mmol) in dichloromethane (11 mL) wasadded p-toluenesulfonyl chloride (3.85 g, 20.2 mmol). The reaction wasstirred at 0° C. for 20 min and at ambient temperature for an additional15.5 h. The solution was diluted with dichloromethane (100 mL) and waswashed sequentially with hydrochloric acid (100 mL, 2 M), water (50 mL)and brine (50 mL). The organic solution was dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography with hexanes/ethyl acetate (2:1to 3:2) to afford (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate(3.40 g, 73%) as a colorless solid: mp 53-54° C. (dichloromethane); ¹HNMR (300 MHz, CDCl₃) δ7.79 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H),4.02 (dd, J=10.8, 5.4 Hz, 1H), 3.95 (dd, J=10.5, 4.5 Hz, 1H), 3.82-3.50(m, 6H), 3.35 (dd, J=11.6, 9.8 Hz, 1H), 2.45 (s, 3H); MS (ES+) m/z 295.0(M+23).

Preparation 36 Synthesis of (S)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate

Following the procedure as described in PREPARATION 35, and makingnon-critical variations using (R)-(1,4-dioxan-2-yl)methanol (Kim, H. Y.,et al., Bioorg. Med. Chem. Lett. (2005), 15:3207-11) to replace(S)-(1,4-dioxan-2-yl)methanol, (S)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate was obtained (79%) as a colorless solid: mp53-55° C. (dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ7.78 (d, J=8.1 Hz,2H), 7.34 (d, J=8.1 Hz, 2H), 4.01 (dd, J=10.5, 5.4 Hz, 1H), 3.94 (dd,J=10.4, 4.7 Hz, 1H), 3.82-3.50 (m, 6H), 3.34 (dd, J=11.2, 10.1 Hz, 1H),2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ145.2, 132.7, 130.0, 128.1, 72.4,68.8, 67.8, 66.5, 66.4, 21.8; MS (ES+) m/z 294.9 (M+23).

Preparation 37 Synthesis of7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of sesamol (7.32 g, 53.1 mmol) in anhydroustetrahydrofuran (150 mL) were added a solution of isopropylmagnesiumchloride (2.0 M in tetrahydrofuran, 30.1 mL, 60.2 mmol) at 0° C. undernitrogen. The reaction mixture was stirred at 0° C. for 30 min, followedby the addition of 7-bromo isatin (8.0 g, 35.4 mmol). The suspendedmixture was stirred at ambient temperature for 16 h. The reactionmixture was diluted with a saturated aqueous solution of ammoniumchloride (300 mL) and ethyl acetate (250 mL), and the phases wereseparated. The aqueous phase was extracted with ethyl acetate (200 mL),and the combined organic solution was washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Thecrude solid was triturated with diethyl ether, filtered and dried underthe reduced pressure to afford7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(9.8 g, 77%) as a light yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.64(s, 1H), 9.18 (s, 1H), 7.33 (dd, J=7.8, 1.4 Hz, 1H), 7.21 (s, 1H),6.84-6.75 (m, 2H), 6.54 (s, 1H), 6.21 (s, 1H), 5.92 (dd, J=6.1, 0.8 Hz,2H); MS (ES+) m/z 363.8 (M+1), 365.8 (M+1).

B. Synthesis of7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of7-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(9.50 g, 27.3 mmol) in trifluoroacetic acid (24 mL) at 0° C. was addedtriethyl silane (6.12 g, 52.8 mmol). The mixture was stirred at ambienttemperature for 3 h. The reaction was quenched by the addition ofhexanes and diethyl ether mixture (2:1, 300 mL). The precipitate wasfiltered, washed with hexanes and ether mixture (100 mL). The solid wasdried under reduced pressure to afford7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(8.40 g, 93%) as an off-white powder: ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 9.26 (s, 1H), 7.33-7.31 (m, 1H), 6.90-6.78 (m, 2H), 6.68 (s,1H), 6.38 (s, 1H), 5.91 (d, J=1.0 Hz, 2H), 4.75 (s, 1H); MS (ES+) m/z347.9 (M+1), 349.9 (M+1).

C. Synthesis of7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

To a mixture of7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(8.40 g, 24.1 mmol), para-formaldehyde (2.88 g, 96.0 mmol) and water (80mL) was added sodium hydroxide (3.84 g, 96.0 mmol) at 0° C. The darkgreen solution was stirred at 0° C. for 4 h. The mixture was acidifiedwith 3 N hydrochloride to pH 4 and extracted with ethyl acetate (3×100mL). The combined ethyl acetate solution was washed with 25% ammoniumchloride solution (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate and concentrated in vacuo to dryness. The residue was treatedwith toluene (300 mL) to give an off white precipitate. The precipitatewas filtered and dried under reduced pressure to give7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(4.80 g, 53%): ¹H NMR (300 MHz, DMSO-d₆) δ10.48 (s, 1H), 9.16 (s, 1H),7.27 (dd, J=8.0, 1.0 Hz, 1H), 7.01 (s, 1H), 6.87-6.74 (m, 2H), 6.22 (s,1H), 5.91 (s, 2H), 5.03 (br, 1H), 4.12 (d, J=10.0 Hz, 1H), 3.85 (d,J=10.0 Hz, 1H); MS (ES−) m/z 376 (M−1), 378 (M−1).

Preparation 38 Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one

To a pale yellow solution of 4-(benzyloxy)phenol (9.01 g, 45.0 mmol) inanhydrous tetrahydrofuran (100.0 mL) was added isopropylmagnesiumchloride (26.3 mL, 52.5 mmol, 2.0 M solution in tetrahydrofuran) at 0°C. The reaction solution was stirred for 0.5 h followed by the additionof 1-((5-chlorothiophen-2-yl)methyl)indoline-2,3-dione (8.31 g, 30.0mmol) in portions. The reaction mixture was stirred for 16 h at ambienttemperature. The reaction was quenched by the addition of saturatedammonium chloride solution (50.0 mL) and concentrated in vacuo todryness. The residue was diluted with ethyl acetate (100 mL), washedwith saturated ammonium chloride solution (2×25.0 mL), brine (2×25 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was purified by columnchromatography with ethyl acetate to afford3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one(4.90 g, 28%) as a colourless solid: mp 174-175° C.; ¹H NMR (300 MHz,CDCl₃) δ8.45 (br, 1H), 7.40-7.27 (m, 7H), 7.14 (dd, J=7.5, 7.5 Hz, 1H),6.92 (d, J=2.9 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.79 (d,J=3.7 Hz, 1H), 6.70 (d, J=3.7 Hz, 1H), 6.43 (d, J=2.9 Hz, 1H), 4.86(ABq, 2H), 4.84 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.3, 152.6,149.790, 141.7, 136.8, 135.8, 130.4, 130.1, 129.1, 128.6, 127.9, 127.6,126.3, 126.2, 126.0, 125.9, 124.3, 120.2, 116.3, 114.4, 109.6, 79.1,70.6, 39.2; MS (ES+) m/z 478.2 (M−1), 476.2 (M−1).

B. Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one

To a solution of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxy-1,3-dihydro-2H-indol-2-one(4.90 g, 10.3 mmol) in dichloromethane (100.0 mL) were addedtrifluoroacetic acid (12.9 g, 113.2 mmol) and triethylsilane (13.2 g,113.2 mmol). The reaction mixture was stirred at ambient temperature for4 h, then concentrated in vacuo to dryness. The gummy residue wasdiluted with ethyl acetate (100.0 mL), washed with water (3×100.0 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was triturated withdiethyl ether, filtered and dried to afford3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one(2.90 g, 61%) as a colourless solid: mp 173-175° C.; ¹H NMR (300 MHz,CDCl₃) δ9.11 (s, 1H), 7.3-7.27 (m, 5H), 7.18 (dd, J=7.5, 7.5 Hz, 1H),7.09 (d, J=3.8 Hz, 1H), 7.06 (dd, J=7.9 Hz, 1H), 6.97-6.86 (m, 3H),6.79-6.68 (m, 3H), 5.04 (ABq, 2H), 4.91 (s, 2H), 4.84 (s, 1H); ¹³C NMR(75 MHz, CDCl₃) δ175.9, 151.5, 149.7, 142.8, 138.8, 137.8, 130.2, 128.8,128.2, 128.1, 128.1, 128.0, 127.4, 126.8, 125.2, 124.2, 122.7, 117.6,117.6, 116.3, 114.9, 109.1, 70.2, 48.1, 38.6; MS (ES+) m/z 464.3 (M+1),462.3 (M+1).

C. Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

To a mixture of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiophen-2-yl)methyl]-1,3-dihydro-2H-indol-2-one(2.80 g, 6.07 mmol), para-formaldehyde (0.73 g, 24.3 mmol) intetrahydrofuran (10.0 mL) was added an aqueous solution of sodiumhydroxide (0.97 g, 24.3 mmol) in water (10.0 mL) at 0° C. The reactionsolution was stirred for 2 h, then quenched by the addition of 10%aqueous hydrochloric acid solution (30.0 mL). The reaction mixture wasextracted with ethyl acetate (3×50 mL). The combined organic solutionwas washed with saturated ammonium chloride (3×50 mL), brine (50.0 mL),dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was triturated withdiethyl ether, filtered and dried to afford3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chlorothiphen-2-yl)methyl]-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(2.71 g, 91%) as a colourless solid: MS (ES+) m/z 494.2 (M+1), 492.3(M+1).

Preparation 39 Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) intetrahydrofuran (100 mL) was added isopropylmagnesium chloride (22.7 mL,2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture wasallowed to stir for 30 min at 0° C., and concentrated in vacuo todryness. Dichloromethane (100 mL) was added, followed by the addition ofa solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol)in dichloromethane (50 mL) at 0° C. The mixture was stirred at roomtemperature for 16 h, and quenched with saturated ammonium chloridesolution. The organic layer was washed with water, dried over sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The obtained solid was recrystallized from ethyl acetate/hexanes toafford3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(19.60 g, 97%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.49-7.43(m, 1H), 7.42-7.25 (m, 13H), 7.23-7.17 (m, 2H), 7.12-7.04 (m, 2H), 6.91(s, 1H), 6.72-6.62 (m, 2H), 6.51-6.44 (m, 1H), 6.39 (dd, J=8.6, 2.4 Hz,1H), 4.99 (s, 2H); MS (ES+) m/z 536.3 (M+23).

B. Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

A mixture of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(10.0 g, 19.5 mmol), triethylsilane (15.6 mL, 97.5 mmol) andtrifluoroacetic acid (15.0 mL, 195 mmol) was mixed and stirred for 20min at 0° C.

The mixture was concentrated under vacuum. The residue was trituratedwith diethyl ether to afford3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(7.40 g, 76%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.25(m, 14H), 7.23-7.17 (m 2H), 7.11-7.02 (m, 2H), 6.95 (s, 1H), 6.81 (d,J=8.6 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.55-6.49 (m, 1H), 6.46 (dd,J=8.6, 2.6 Hz, 1H), 5.09 (s, 1H), 4.99 (s, 2H); MS (ES+) m/z 498.3(M+1).

Preparation 40 Synthesis ofN′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide

To a stirred solution of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(1.30 g, 32.9 mmol) in dimethyl sulfoxide (10 mL) was added 50% wtsolution of hydroxylamine in water (2 mL). The reaction was heated withstirring at 80° C. for 1 h, then cooled to ambient temperature and theproduct was precipitated by adding distilled water (25 mL). The solidwas filtered and air dried to affordN′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide(1.32 g, 93%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.17 (s,1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50(m, 1H), 5.10 (s, 1H); MS (ES+) m/z 428.0 (M+1).

Preparation 41 Synthesis of2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-W-[(cyclopropylcarbonyl)oxy]ethanimidamide

A stirred solution of2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide(0.40 g, 1.0 mmol), diisopropylamine (0.16 g, 1.6 mmol) and cyclopropanecarbonyl chloride (0.16 g, 1.6 mmol) in dichloromethane (20 mL) wasstirred for 16 h at ambient temperature. The colorless solid thatprecipitated from the solution was filtered, washed with water (5 mL)and diethyl ether (5 mL) to afford2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamideas a colorless solid (0.25 g, 53%): ¹H NMR (300 MHz, DMSO-d₆) δ7.31 (dd,J=8.0, 8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.64 (br s, 2H), 6.54 (s,1H), 6.47 (s, 1H), 5.88 (s, 2H), 4.77 (ABq, 2H), 4.43 (ABq, 2H),1.75-1.67 (m, 1H), 0.86-0.73 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) 176.9,171.9, 156.5, 153.6, 148.9, 144.8, 141.9, 130.8, 130.0, 128.6, 117.4,108.8, 104.4, 101.8, 104.5, 101.8, 104.4, 101.8, 93.0, 77.5, 58.4, 11.7,8.45, 8.42; MS (ES+) m/z 456.1 (M+1), 478.1 (M+23).

Preparation 42 Synthesis ofN′-hydroxy-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethanimidamide

To a mixture of2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile(2.00 g, 6.25 mmol) in ethanol (40 mL) and dimethyl sulfoxide (5 mL) wasadded hydroxylamine (25.0 g, 1.6 mL, 50% wt solution in water). Thereaction solution was stirred at ambient temperature for 2 h to form acolourless precipitate. The solid was filtered. The residue was washedwith water (3×20 mL) and dried to affordN′-hydroxy-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethanimidamide(1.88 g, 85%) as a colourless solid: mp 235-238° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.20 (s, 1H), 7.26 (dd, J=7.7, 7.7 Hz, 1H), 7.10 (d, J=7.3Hz, 1H), 6.99 (dd, J=8.6, 8.6 Hz, 2H), 6.65 (s, 1H), 6.28 (s, 1H), 5.89(d, J=1.8 Hz, 2H), 5.49 (s, 2H), 4.70 (ABq, 2H), 4.29 (s, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ 177.1, 155.7, 148.7, 147.9, 143.0, 142.1, 132.3,129.1, 123.7, 123.3, 120.5, 110.0, 103.9, 101.8, 93.6, 80.2, 57.8, 40.3;MS (ES+) m/z 354.18 (M+1), 337.2 (M−17).

Preparation 43 Synthesis of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile

To a solution of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.97 g, 3.46 mmol) in 2-butanone (25 mL) were added cesium carbonate(3.39 g, 10.39 mmol) and α-bromo-m-tolunitrile (0.85 g, 4.33 mmol). Themixture was heated to reflux for 2 h, cooled to ambient temperature, andfiltered. The solid was washed with ethyl acetate. The filtrate wasconcentrated in vacuo, the residue was purified by column chromatographywith ethyl acetate-hexanes (1:5-1:1), followed by recrystallization fromethyl acetate and diethyl ether to afford3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(1.26 g, 92%) as a colorless solid: mp 187-193° C.; ¹H NMR (300 MHz,CDCl₃) δ7.61-7.58 (m, 3H), 7.47-7.44 (m, 1H), 7.25-7.19 (m, 2H),7.07-7.03 (m, 1H), 6.73-6.71 (m, 1H), 6.43-6.41 (m, 2H), 5.11-4.70 (m,4H), 4.53 (d, J=9.0 Hz, 2H), 3.09-2.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ 178.1, 162.0, 161.4, 141.5, 137.5, 132.6, 131.9, 131.6, 130.7, 129.9,128.9, 124.3, 123.9, 120.2, 119.9, 118.7, 118.4, 113.1, 108.8, 93.4,80.5, 72.5, 57.7, 43.4, 29.0; MS (ES+) m/z 394.8 (M+1).

Preparation 44 Synthesis ofN′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide

To a solution of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(1.15 g, 2.92 mmol) in dimethyl sulfoxide (20 mL) was addedhydroxylamine (50% wt in H₂O, 2 mL, 32.67 mmol). The reaction wasstirred at 80° C. for 3 h, cooled to ambient temperature. Theprecipitate was collected by filtration and washed with water anddiethyl ether and dried in vacuo to affordN′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)yl)methyl]benzenecarboximidamide (0.85 g, 68%): ¹H NMR (300 MHz, CDCl₃)δ7.61 (m, 1H), 7.96 (m, 1H), 7.51 (m, 1H), 7.38 (m, 2H), 7.16 (m, 2H),7.01 (m, 1H), 6.75 (m, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.09 (d, 1H,J=15.7 Hz), 4.98 (d, 1H, J=9.0 Hz), 4.83 (m, 3H), 4.70 (d, 1H, J=9.0Hz), 4.49 (t, 2H, J=8.6 Hz), 2.96 (m, 2H); MS (ES+) m/z 427.8 (M+1).

Preparation 45 Synthesis of6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of 6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(3.0 g, 11.8 mmol) in anhydrous N,N-dimethylformamide (30 mL) undernitrogen were added imidazole (1.97 g, 28.9 mmol) and triisopropylsilylchloride (6.03 mL, 28.5 mmol). The reaction mixture was stirred atambient temperature for 16 h. The reaction mixture was concentrated invacuo to dryness. The residue was extracted twice with ethyl acetate (50mL), the combined organic phases were dried over sodium sulfate, and thefiltrate was concentrated and purified by flash chromatography with 30%ethyl acetate in hexanes to give6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.68 g, 69% yield) as colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.48-8.08 (br, 1H), 7.29-6.90 (m, 4H), 6.10 (d, J=8.1 Hz, 1H), 6.50 (d,J=2.1 Hz, 1H), 6.35 (dd, J=8.1, 2.1 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H),4.69 (d, J=9.0 Hz, 1H), 1.34-0.98 (m, 21H).

Preparation 46 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.46 g, 6.0 mmol) in anhydrous N,N-dimethylformamide (10 mL) at 0° C.under nitrogen was added sodium hydride (0.24 g, 6.0 mmol). The abovemixture was stirred at 0° C. for 20 min, then(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (1.69 g, 6.6mmol) was added. The reaction mixture was stirred at ambient temperaturefor 30 min, then heated to 60° C. for 5 h. The reaction was quenchedwith aqueous saturated ammonium chloride (10 mL), poured into water (15mL) and extracted with ethyl acetate (3×40 mL). The combined organicsolution was washed with water (2×50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated. The residue was purified bycolumn chromatography with 25% ethyl acetate in hexanes to afford1-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.70 g, 58%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.33-7.26 (m,1H), 7.14-6.98 (m, 3H), 6.53 (d, J=8.1 Hz, 1H), 6.48 (d, J=2.1 Hz, 1H),6.32 (dd, J=8.1, 2.1 Hz, 1H), 4.95-4.90 (m, 1H), 4.66 (d, J=9.3 Hz, 1H),4.34-4.22 (m, 1H), 4.00-3.66 (m, 4H), 2.10-1.66 (m, 4H), 1.34-0.98 (m,21H); MS (ES+) m/z 494.2 (M+1).

Preparation 47 Synthesis of5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one A. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

To a solution of 3,4-difluorophenol (10.33 g, 79.4 mmol) in anhydroustetrahydrofuran (60 mL) at 0° C. under nitrogen was added isopropylmagnesium chloride (39.7 mL, 79.4 mmol), and the solution was stirred atambient temperature for 3 h. Tetrahydrofuran was removed by rotaryevaporation, and the residue was redissolved in anhydrousdichloromethane (140 mL). The solution was cooled to 0° C. undernitrogen, then N-benzhydryl isatin (13.77 g, 43.9 mmol) was added andthe reaction mixture was allowed to warm to ambient temperature. After 3days, the reaction was quenched with aqueous saturated ammonium chloride(60 mL) and concentrated in vacuo. The residue was re-dissolved in ethylacetate (150 mL) and washed with water (2×100 mL) and brine (100 mL),dried over sodium sulfate, filtered, and concentrated. The residue wasprecipitated from diethyl ether to yield3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(12.08 g, 61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.23 (brs, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90(s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H),6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).

B. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

To a solution of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(11.72 g, 26.4 mmol) in trifluoroacetic acid (60 mL) under nitrogen wasadded triethylsilane (10.55 mL, 66.0 mmol), and the reaction mixture wasstirred for 16 h. Following concentration in vacuo, the residue waspurified by column chromatography (30% ethyl acetate in hexanes).Precipitation from diethyl ether/hexanes followed by filtration yielded3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(6.29 g, 56%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.27 (brs, 1H), 7.37-7.12 (m, 12H), 6.94 (s, 1H), 6.87 (dd, J=11.3, 7.1 Hz, 1H),6.76 (dd, J=11.2, 8.9 Hz, 1H), 6.58-6.56 (m, 1H), 5.12 (s, 1H); MS (ES+)m/z 428.2 (M+1).

C. Synthesis of1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(6.30 g, 14.7 mmol) in anhydrous tetrahydrofuran (120 mL) under argonwas added cesium carbonate (14.4 g, 44.2 mmol), followed by the additionof chloroiodomethane (3.21 mL, 44.2 mmol) dropwise. After 20 h, thereaction mixture was concentrated in vacuo and re-dissolved in ethylacetate (50 mL) and water (50 mL). The aqueous layer was extracted withethyl acetate (6×50 mL). Some product was filtered off as a colorlessprecipitate. The combined organic solution was washed with water (2×150mL) and brine (150 mL), dried over sodium sulfate, filtered, andconcentrated. Precipitation from diethyl ether/hexanes afforded1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(4.51 g, 70%) as a colorless solid: mp 213-216° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.41-7.26 (m, 10H), 7.15-7.12 (m, 1H), 7.08-6.97 (m, 3H), 6.78(dd, J=10.5, 6.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (dd, J=9.0, 7.8Hz, 1H), 5.03 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H); ¹³C NMR (75MHz, CDCl₃) δ 176.8, 156.6 (d, J=11.0 Hz), 151.2 (dd, J_(C-F)=248.2,14.5 Hz), 145.6 (dd, J_(C-F)=241.5, 13.85 Hz), 141.7, 137.4, 137.1,131.5, 128.8, 128.8, 128.7, 128.3, 128.3, 128.1, 128.0, 124.2 (dd,J=6.4, 3.3 Hz), 123.8, 123.3, 112.4, 111.5 (dd, J=20.4, 1.6 Hz), 100.1(d, J=22.4), 80.8, 58.9, 57.5; MS (ES+) m/z 440.2 (M+1), 462.2 (M+23).

D. Synthesis of 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of1-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(6.06 g, 13.8 mmol) in methanol (100 mL), ethyl acetate (25 mL) andacetic acid (1 mL) under argon in a steel bomb was added palladium (20%on activated carbon, nominally 50% H₂O, 2.0 g, 3.76 mmol). The bomb wasput under hydrogen (50 psi) and heated at 65° C. for 16 h. The reactionmixture was filtered through celite and washed with ethyl acetate (15mL) and methanol (50 mL). The filtrate was concentrated and the residuewas precipitated from methanol. Filtration afforded5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.63 g, 96%) asa colorless solid: mp>200° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (s, 1H),7.32-7.27 (m, 1H), 7.15-7.05 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.79 (dd,J=10.3, 6.3 Hz, 1H), 6.62 (dd, J=9.0, 8.0 Hz, 1H), 5.00 (d, J=9.2 Hz,1H), 4.73 (d, J=9.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 179.7, 156.70 (d,J=10.9), 151.3 (dd, J_(C-F)=248.7, 14.3 Hz), 145.7 (dd, J_(C-F)=241.6,13.8 Hz), 140.3, 131.6, 129.4, 124.0, 123.7, 123.4 (dd, J=6.3, 3.1 Hz),111.9 (d, J=20.4 Hz), 110.7, 100.1 (d, J=22.4 Hz), 80.7, 58.4; MS (ES+)m/z 274.2 (M+1).

Preparation 48 Synthesis ofN′-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1-yl)propanimidamide

To a stirred solution of3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanenitrile(2.00 g, 6.0 mmol) in dimethyl sulfoxide (15.0 mL) was addedhydroxylamine (50% wt solution in water, 1.6 mL, 24 mmol). The reactionwas stirred at ambient temperature for 16 h, then the product wasprecipitated upon addition of water/ethanol (3:1, 100 mL). The solventwas decanted and the remaining solid was triturated in distilled water(75 mL). The solid was filtered and air-dried to affordN′-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)propanimidamideas a colorless solid (2.00 g, 91%): MS (ES+) m/z 368.2 (M+1).

Preparation 49 Synthesis of4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of 1,3-benzodioxol-5-ol (4.86 g, 22.0 mmol) in anhydroustetrahydrofuran (100 mL) was added dropwise a solution of isopropylmagnesium chloride (49.6 mmol, 24.8 mL, 2.0 M solution intetrahydrofuran) over 10 min at 0° C. The reaction mixture was stirredfor 30 min upon which time 4-chloroisatin (4.00 g, 22.0 mmol) was addedin one portion. The reaction mixture was stirred at ambient temperaturefor 2 h and quenched by the addition of 10% aqueous hydrochloric acid(25.0 mL) and the mixture was concentrated in vacuo to dryness. Theresidue was diluted with ethyl acetate (100 mL), washed with saturatedammonium chloride (3×30.0 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas triturated with hot diethyl ether to afford4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(6.70 g, 95%) as a beige solid: mp 250-253° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.30, (s, 1H), 9.04 (s, 1H), 7.20 (s, 1H), 7.12 (t, J=8.0Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.45 (s, 1H),6.17 (s, 1H), 5.88 (d, J=6.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.1,148.6, 147.0, 145.6, 139.6, 130.6, 130.1, 129.6, 122.3, 118.6, 108.9,108.4, 101.1, 97.4, 75.8; MS (ES−) adz 304.2 (M−17), 302.2 (M−17).

Preparation 50 Synthesis of4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one

To a solution of4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(6.00 g, 18.8 mmol) in anhydrous dichloromethane (70.0 mL) was addedtrifluoroacetic acid (30.7 g, 269 mmol) and triethylsilane (18.0 mL,13.1 g, 113 mmol) at ambient temperature. The reaction mixture wasstirred at ambient temperature for 2 h. The reaction mixture wasquenched with water (100.0 mL) and the solid was filtered. The solid wastriturated with diethyl ether to afford4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(4.71 g, 83%) as a colourless solid: mp 210-225° C. (dec.); MS (ES+) m/z304.1 (M+1), 302.1 (M+1).

Preparation 51 Synthesis of4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one

To a suspension of4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(4.5 g, 14.9 mmol), para-formaldehyde (1.78 g, 59.4 mmol) in water (50.0mL) was added the aqueous solution of sodium hydroxide (2.38 g, 59.4mmol) in water (10.0 mL). The reaction mixture was stirred at 0° C. for2 h and quenched with 10% hydrochloric acid (50.0 mL). The precipitatewas filtered and washed with water (100.0 mL). The filtrate wasextracted with ethyl acetate (3×50.0 mL). The combined organic solutionwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was triturated with ethylacetate and diethyl ether to afford4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(3.91 g, 72%) as a colourless solid: mp>210° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.04 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.99 (d, J=7.7 Hz, 1H),6.86 (s, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.18 (s, 1H), 5.87 (d, J=11.0 Hz,2H), 5.03 (q, J=10.8 Hz, 2H), 4.86 (br, 1H), 4.64 (ABq, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ 177.9, 150.3, 146.9, 146.8, 139.9, 129.1, 129.0, 128.6,122.7, 116.0, 108.8, 107.6, 101.2, 97.7, 63.6, 63.3, 56.6; MS (ES+) m/z364.2 (M+1), 346.2 (M−17).

Preparation 52 Synthesis of4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(3.63 g, 10.0 mmol) in anhydrous tetrahydrofuran (100.0 mL) was addedtributylphosphine (2.53 g, 12.5 mmol) at 0° C. followed by the solutionof di-tert-butyl azodicarboxylate (2.88 g, 12.5 mmol) in anhydroustetrahydrofuran (25.0 mL). The reaction solution was stirred at 0° C.for 1 h followed by the addition of ammonium hydroxide (100.0 mL). Thereaction mixture was continued to stir for another 2 h. The reaction wasquenched with 10% aqueous solution of hydrochloric acid (100.0 mL). Thereaction solution was extracted with ethyl acetate (3×100.0 mL). Thecombined organic solution was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo to dryness. The residuewas purified by flash chromatography with ethyl acetate in hexanes toafford4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.98 g, 31%) as a colourless solid: mp 175-185° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.81 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.2 Hz,1H), 6.86 (d, J=7.1 Hz, 1H), 6.59 (s, 1H), 6.28 (s, 1H), 5.90 (d, J=2.5Hz, 2H), 4.74 (ABq, J=9.5 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.4,157.0, 148.8, 144.2, 141.9, 130.9, 130.3, 129.2, 123.0, 117.5, 109.4,103.3, 101.9, 93.3, 77.8, 58.9; MS (ES+) m/z 318.3 (M+1), 316.3 (M+1).

Preparation 53 Synthesis of2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-W-hydroxyethanimidamide

To a solution of4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile(1.81 g, 5.10 mmol) in ethanol (25.0 mL) and dimethylsulfoxide (3.0 mL)was added hydroxylamine (0.67 g, 20.4 mL) at ambient temperature. Theyellow reaction solution was stirred for 2 h upon which time yellowprecipitate formed. The precipitate was filtered, washed with water(100.0 mL) and dried under vacuum to afford2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N-hydroxyethanimidamide(1.54 g, 78%) as a fluffy yellow solid: mp 180-185° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.20 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.01 (d, J=3.8 Hz, 1H),6.98 (d, J=3.5 Hz, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 5.60 (d, J=3.8 Hz,2H), 5.54 (br, 2H), 4.78 (ABq, J=9.6 Hz, 2H), 3.68 (s, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.8, 156.6, 148.9, 147.7, 145.1, 141.9, 130.8, 129.9,128.5, 123.5, 117.5, 109.1, 103.7, 101.9, 93.2, 77.5, 58.4, 40.9; MS(ES+) m/z 388.1 (M+1).

Preparation 54 Synthesis of1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(1.37 g, 4.89 mmol), 5-(chloromethyl)-1,3-oxazolidin-2-one (1.34 g, 5.38mmol) and cesium carbonate (2.39 g, 7.34 mmol) in N,N-dimethylformamide(8.0 mL) was stirred at ambient temperature for 11 h and filtered. Thesolid was washed with ethyl acetate and the filtrate was washed withwater (3×15 mL), dried over sodium sulfate and filtered. The filtratewas concentrated in vacuo to dryness. The residue was purified by columnchromatography to afford1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.56 g, 25%): mp 195-202° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.30 (m,1H), 7.17-7.04 (m, 3H), 6.50 (s, 1H), 6.12 (s, 1H), 5.84 (s, 2H), 5.27(br, 1H), 5.02-4.96 (m, 1H), 4.91-4.87 (m, 1H), 4.68-4.64 (m, 1H),4.14-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 178.9, 158.5, 155.9, 149.0, 142.4, 142.2, 131.7, 129.4,124.0, 123.9, 119.2, 109.6, 102.8, 101.6, 93.7, 80.3, 74.9, 58.1, 43.5,43.1; MS (ES+) m/z 403.2 (M+23), 381.2 (M+1).

Preparation 55 Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

To a solution of 1,3-benzodioxol-5-ol (9.63 g, 69.7 mmol) in anhydroustetrahydrofuran (200 mL) was added dropwise a solution of isopropylmagnesium chloride (92.9 mmol, 46.5 mL, 2.0 M solution intetrahydrofuran) over 30 min at 0° C. 7-Trifluoromethylisatin (4.00 g,22.0 mmol) was added in one portion. The reaction mixture was stirred atambient temperature for 4 h and the reaction was quenched by theaddition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture wasconcentrated in vacuo to dryness. The residue was diluted with ethylacetate (200 mL), washed with saturated ammonium chloride (3×30.0 mL),brine (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue wastriturated with hot diethyl ether to afford3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(13.6 g, 83%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.21 (s, 1H),7.38 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.95 (dd,J=7.7, 7.7 Hz, 1H), 6.57 (s, 1H), 6.17 (s, 1H), 5.89 (d, J=6.2 Hz, 2H);¹³C NMR (75 MHz, DMSO-d₆) δ 179.2, 148.6, 147.3, 141.0, 139.9, 135.7,127.9, 125.3, 124.3, 121.7, 119.8, 110.1, 107.2, 101.2, 97.7, 73.9; MS(ES−) m/z 352.2 (M−1).

B. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

To a solution of3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(7.06 g, 20.0 mmol) in anhydrous trifluoroacetic acid (21.0 mL, 9.12 g,80 mmol) was added triethylsilane (12.8 mL, 9.30 g, 80.0 mmol) atambient temperature. The reaction mixture was stirred at ambienttemperature for 0.5 h. The reaction mixture was quenched with water(50.0 mL). The mixture was extracted with ethyl acetate (2×150 mL). Theorganic solution was washed with saturated ammonium chloride (3×75 mL),dried over sodium sulfate and filtered. The filtrate was concentrated invacuo to dryness. The residue was triturated with diethyl ether toafford3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(5.94 g, 88%) as colourless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s,1H), 9.25 (br, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.12 (d, J=7.3 Hz, 1H), 6.98(dd, J=7.7, 7.7 Hz, 1H), 6.71 (s, 1H), 5.88 (s, 2H), 4.65 (s, 1H); ¹³CNMR (75 MHz, DMSO-d₆) δ 178.7, 150.5, 147.4, 140.5, 140.1, 133.3, 127.8,124.3, 124.2, 121.6, 115.5, 110.8, 110.3, 101.3, 98.2, 48.1; MS (ES+)m/z 338.3 (M+1).

C. Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one

To a suspension of3-(6-hydroxy-1,3-benzodioxol-5-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(5.64 g, 16.7 mmol), para-formaldehyde (1.78 g, 59.4 mmol) intetrahydrofuran (20.0 mL) and water (50.0 mL) was added the aqueoussolution of sodium hydroxide (2.68 g, 66.9 mmol) in water (30.0 mL). Thereaction mixture was stirred at 0° C. for 1 h and quenched with 10%hydrochloric acid (50.0 mL). The mixture was extracted with ethylacetate (3×50.0 mL). The combined organic solution was washed withsaturated ammonium chloride (3×50 mL), dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo to dryness.The residue was purified by column chromatography to afford3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(4.56 g, 73%) as a fluffy solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s,1H), 9.16 (s, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 7.01(s, 1H), 6.94 (dd, J=7.7, 7.7 Hz, 1H), 6.18 (s, 1H), 5.88 (s, 2H), 5.03(br, 1H), 3.97 (ABq, J=9.9 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 180.5,150.3, 146.8, 141.5, 140.0, 136.0, 127.5, 123.8, 121.0, 117.7, 109.7,108.4, 101.2, 97.9, 60.2, 55.2; MS (ES+) m/z 390.2 (M+1).

Preparation 56 Synthesis of7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-7-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one(4.10 g, 11.7 mmol) in ethyl acetate (100.0 mL) was addedtributylphosphine (3.4 mL, 2.83 g, 13.9 mmol) at 0° C. followed by thesolution of di-tert-butyl azodicarboxylate (3.22 g, 13.9 mmol) in ethylacetate (50.0 mL). The reaction solution was stirred at 0° C. for 30 minfollowed by the addition of 10% hydrochloric acid (50.0 mL). Thereaction solution was washed with 10% hydrochloric acid (2×50.0 mL),saturated ammonium chloride (3×50 mL) and brine (3×50 mL). The organicsolution was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby flash chromatography to afford7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(3.59 g, 88%): mp 245-248° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 11.02 (s,1H), 7.50 (d, J=7.9 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.11 (dd, J=7.5,7.5 Hz, 1H), 6.66 (s, 1H), 6.32 (s, 1H), 5.90 (d, J=3.1 Hz, 2H), 4.74(ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 179.4, 156.0, 148.9, 139.7,134.9, 128.3, 125.8, 125.7 (m), 122.9, 119.7, 112.0, 111.4 (m), 103.6,101.9, 93.7, 80.4, 57.5; MS (ES+) m/z 350.3 (M+1).

Preparation 57 Synthesis of tert-butyl3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate

To a mixture ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.96 g, 3.41mmol) in 2-butanone (17 mL) and acetone (17 mL) were added cesiumcarbonate (3.79 g, 11.6 mmol) and N-Boc-3-(2-bromoethyl)piperidine (1.00g, 3.42 mmol) at ambient temperature. The mixture was stirred at ambienttemperature for 16 h. The reaction mixture was filtered and washed withacetone (2×50 mL). The filtrate was concentrated in vacuo to dryness.The residue was purified by column chromatography with ethyl acetate inhexanes (10% to 30% gradient) to give tert-butyl3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate(1.48 g, 88%) as a white powder: mp 64-67° C. (diethyl ether/hexanes);¹H NMR (300 MHz, CDCl₃) δ 7.30 (dt, J=7.8, 0.9 Hz, 1H), 7.16 (d, J=7.3Hz, 1H), 7.50 (dt, J=7.5, 0.7 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.50 (s,1H), 6.10 (d, J=1.7 Hz, 1H), 5.86 (dd, J=6.0, 1.0 Hz, 2H), 4.90 (dd,J=9.0, 0.6 Hz, 1H), 4.65 (dd, J=9.0, 3.0 Hz, 1H), 3.90-3.69 (m, 4H),2.97-2.86 (m, 1H), 2.77-2.68 (m, 1H), 1.96-1.92 (m, 1H), 1.76-1.16 (m,15H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 155.8, 154.8, 148.8, 142.3,142.2, 142.1, 132.4 (2), 128.9, 124.0, 123.2, 119.4 (2), 108.5, 102.9,101.4, 93.6, 80.4, 79.4, 58.1, 38.2, 33.5, 30.7, 30.7, 30.6, 30.5, 28.4,24.3; MS (ES+) m/z 515.4 (M+23).

Preparation 58 Synthesis of3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine

To a solution of tert-butyl3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate(1.48 g, 3.0 mmol) in dichloromethane (20 mL) was added trifluoroaceticacid (4 mL) at 0° C. The mixture was stirred at ambient temperature for2 h and concentrated in vacuo to dryness. The residue was diluted indichloromethane (100 mL) and washed with saturated aqueous sodiumbicarbonate solution (2×30 mL), water (30 mL), and dried over anhydroussodium sulfate, filtered and concentrated in vacuo to dryness to give3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine(0.72 g, 60%): MS (ES+) m/z 393.4 (M+1).

Preparation 59 Synthesis of ethyl5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate

To a solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (4.26 g,15.10 mmol) in 2-butanone (120 mL) was added cesium carbonate (14.76 g,45.30 mmol) and ethyl5-(bromomethyl)-2-(trifluoromethyl)furan-3-carboxylate (Lyalin, V. V.;et al., Zhurnal Organicheskoi Khimii (1984), 20(4):846) (4.80 g, 15.90mmol). The reaction mixture was heated at 60° C. to 70° C. for 18 h,cooled to ambient temperature and filtered. The solid was washed withethyl acetate. The filtrate was concentrated in vacuo, the residue waspurified by column chromatography with ethyl acetate and hexanes toafford ethyl5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate(4.65 g, 61%): mp 162-164° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.23-7.17 (m,2H), 7.12-7.06 (m, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.50 (s,1H), 5.86-5.85 (m, 2H), 5.05-4.87 (m, 3H), 4.68-4.64 (m, 1H), 4.31 (q,J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2,160.4, 155.9, 150.6, 149.1, 143.5, 142.5, 141.1, 132.0, 129.1, 124.2,124.0, 120.7, 120.0, 119.0, 116.4, 111.1, 108.7, 103.0, 101.6, 93.7,80.4, 61.7, 58.2, 36.7, 13.9; MS (ES+) m/z 502.1 (M+1).

Preparation 60 Synthesis of5-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)-2-(trifluoromethyl)furan-3-carboxylicacid

To a solution of ethyl5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate(1.30 g, 2.59 mmol) in ethanol (8 mL) and water (1.7 mL) was addedsodium hydroxide (0.12 g, 3.00 mmol). The reaction mixture was heated atreflux for 45 min, concentrated in vacuo to remove ethanol. To theresidue was added water (15 mL) and the mixture was acidified to pH-3 by10% hydrochloric acid at 0° C. The resulting mixture was extracted withethyl acetate (3×50 mL). The organic layer was washed with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo to give5-((2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)methyl)-2-(trifluoromethyl)furan-3-carboxylicacid (1.03 g, 84%): mp 195-197° C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.13-7.26 (m, 1H), 7.17-7.15 (m, 2H), 7.05-7.00 (m, 2H), 6.67 (s, 1H),6.09 (s, 1H), 5.90-5.88 (m, 2H), 5.11-4.96 (m, 2H), 4.80-4.66 (m, 2H);¹³C NMR (75 MHz, DMSO-d₆) δ 177.0, 161.9, 155.8, 152.3, 148.9, 142.2,141.9, 141.5, 132.1, 129.3, 124.1, 123.8, 122.2, 120.6, 120.1, 117.0,111.8, 109.7, 103.1, 101.9, 93.8, 80.1, 57.9, 36.7; MS (ES−) m/z 472.0(M−1).

Preparation 61 Synthesis of1-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A suspended mixture of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.12 g, 4.0 mmol), 4-bromobenzyl bromide (1.00 g, 4.0 mmol) and cesiumcarbonate (6.50 g, 20.0 mmol) in butanone (20 mL) was refluxed for 3 hunder nitrogen. The reaction mixture was cooled to ambient temperatureand filtered. The solid was washed with acetone (50 mL). The filtratewas concentrated in vacuo to dryness. The residue was purified by columnchromatography with a 20% to 80% gradient of ethyl acetate in hexanes toafford1-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.60 g, 89%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.49-6.98 (m, 7H), 6.75 (d, J=7.7 Hz, 1H), 6.43 (s, 1H), 6.42 (s, 1H),4.89 (ABq, 2H), 4.82 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.08-2.90 (m,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.9, 161.9, 161.3, 141.8, 134.8,132.7, 132.0, 129.2, 128.7, 124.0, 123.6, 121.7, 120.0, 120.0, 118.8,109.0, 93.3, 80.6, 72.4, 57.7, 43.6, 29.0; MS (ES+) m/z 448.1 (M+1),450.1 (M+1).

Preparation 62 Synthesis of methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate

A suspended mixture of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.00 g, 3.3 mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (2.00g, 11.4 mmol) and cesium carbonate (4.00 g, 12.3 mmol) in butanone (50mL) was refluxed for 5 h under nitrogen. The reaction mixture was cooledto ambient temperature and filtered. The solid was washed with acetone(50 mL). The filtrate was concentrated in vacuo to dryness. The residuewas purified by column chromatography with a 30% to 70% gradient ofethyl acetate in hexanes to afford methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate(0.88 g, 61%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s,1H), 7.27-6.91 (m, 4H), 6.53 (s, 1H), 6.38 (s, 1H), 5.12 (ABq, 2H), 4.81(ABq 2H), 4.51 (t, J=8.7 Hz, 2H), 3.89 (s, 3H), 3.04-2.91 (m, 2H); ¹³CNMR (75 MHz, DMSO-d₆) δ177.6, 161.9, 161.2, 161.2, 159.2, 145.0, 141.0,133.6, 132.5, 129.0, 124.1, 120.1, 119.9, 199.1, 108.8, 93.2, 80.5,72.4, 57.7, 52.3, 37.2, 29.0; MS (ES+) m/z 419.2 (M+1).

Preparation 63 Synthesis of2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid

A suspended mixture of methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate(0.88 g, 2.1 mmol) and sodium hydroxide (4.00 g, 10.0 mmol) in water (50mL) and methanol (50 mL) was stirred at 60° C. for 2 h. The reactionmixture was concentrated in vacuo to remove most of methanol andacidified with concentrated hydrochloric acid to pH 1-2. The solidresidue was filtered off, washed with water (50 mL) and dried in vacuoto afford2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid (0.64 g, 75%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.24 (s, 1H), 7.29-6.95 (m, 4H), 6.55 (s, 1H), 6.37 (s, 1H), 5.08 (ABq,2H), 4.74 (ABq, 2H), 4.44 (t, J=8.7 Hz, 2H), 3.01-2.80 (m, 2H); MS (ES−)m/z 403.4 (M−1).

Preparation 64 Synthesis of methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate

A suspended mixture ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.60 g, 5.70mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (1.00 g, 5.70 mmol)and cesium carbonate (3.71 g, 11.4 mmol) in tetrahydrofuran (10 mL) wasrefluxed for 16 h. The reaction mixture was cold down to ambienttemperature and concentrated in vacuo. The residue was treated withwater (20 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic solution was dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby column chromatography with a 20% to 30% gradient of ethyl acetate inhexanes to afford methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate(2.19 g, 92%) as a colorless solid: mp 183-185° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.86 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H),7.09 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.41 (S,1H), 5.90 (d, J=2.1 Hz, 2H), 5.23-5.17 (m, 2H), 4.74 (ABq, 2H), 3.74 (s,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.2, 161.3, 160.2, 155.6, 148.8,146.9, 142.3, 142.0, 132.8, 132.4, 129.4, 124.1, 123.9, 120.4, 109.7,103.9, 101.9, 93.7, 80.0, 57.9, 52.3, 37.4; MS (ES+) m/z 421.2 (M+1).

Preparation 65 Synthesis of2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid

To a solution of methyl2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate(1.17 g, 2.79 mmol) in tetrahydrofuran (20 mL) was added a solution ofsodium hydroxide (0.45 g, 11.1 mmol) in water (5 mL). The mixture wasstirred at reflux for 16 h. After cooling down to ambient temperature,the mixture was acidified with concentrated hydrochloric acid (2 mL).The reaction mixture was concentrated in vacuo to remove most oftetrahydrofuran and extracted with ethyl acetate (3×25 mL). The combinedorganic solution was dried over sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue wastriturated with diethyl ether and ethyl acetate to afford2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid (0.65 g, 58%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ13.07 (br, 1H), 8.74 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.17 (d, J=6.6 Hz,1H), 7.10 (d, J=7.8 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.34(s, 1H), 6.04 (s, 2H), 5.20-5.08 (m, 2H), 4.73 (ABq, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ177.1, 162.2, 159.9, 155.7, 148.8, 146.4, 142.2, 142.1,133.8, 132.2, 129.4, 124.1, 123.9, 120.3, 109.7, 103.8, 101.9, 93.7,80.0, 57.8, 31.2; MS (ES+) m/z 407.1 (M+1).

Preparation 66 Synthesis of4′-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one

To a stirred solution of4′-bromo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one(0.64 g, 1.8 mmol) in 2-butanone (25 mL) was added cesium carbonate(1.75 g, 5.3 mmol) followed by 2-(bromomethyl)-5-(trifluoromethyl)furan(0.51 g, 2.2 mmol). The mixture was refluxed for 16 h, cooled to ambienttemperature, filtered and concentrated in vacuo to dryness. The residuewas subjected to column chromatography (hexanes/ethyl acetate from 3:1to 1:1) to afford4′-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one(0.82 g, 90%) as a colorless solid: mp 165-167° C.; ¹H NMR (300 MHz,CDCl₃) δ7.27-7.10 (m, 2H), 6.92 (td, J=6.9, 1.8 Hz, 1H), 6.77-6.70 (m,1H), 6.44-6.33 (m, 3H), 5.15-4.96 (m, 2H), 4.91-4.76 (m, 2H), 4.53 (dt,J=8.6, 1.9 Hz, 2H), 2.98 (t, J=8.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃)δ177.3, 162.4, 162.2, 151.6, 143.4, 141.8 (q, J=43.0 Hz), 130.2, 127.7,120.0, 119.7, 118.8 (q, J=267.1 Hz), 118.4, 117.0, 112.6, 109.5, 107.7,92.9, 77.1, 72.4, 59.0, 37.0, 28.9; MS (ES+) m/z 505.8 (M+1), 507.8(M+1).

Preparation 67 Synthesis of6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one A.Synthesis of1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

To a solution of 3-fluoro-4-methoxyphenol (Niemann, M. B. J. Am. Chem.Soc. (1941), 63:609) (4.60 g, 32.4 mmol) in tetrahydrofuran (60 mL) at5° C. was added a 2 M solution of isopropylmagnesium chloride intetrahydrofuran (18.0 mL, 36.0 mmol). Tetrahydrofuran was removed underreduced pressure and dichloromethane (60 mL) was added. To the solutionwas added a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (8.00 g,25.5 mmol) in dichloromethane (60 mL) at 5° C. and the reaction mixturewas stirred at ambient temperature for 16 h. The reaction mixture wasquenched with saturated ammonium chloride solution (5 mL). The reactionmixture was dried over magnesium sulfate, filtered and evaporated underreduced pressure. The residue was subjected to column chromatographywith 40% to 90% gradient of ethyl acetate in hexanes to afford1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(6.60 g, 57%) as a pink solid: MS (ES+) m/z 438.3 (M−17).

B. Synthesis of1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(6.60 g, 14.5 mmol) in dichloroethane (100 mL) were added triethylamine(4.55 g, 45.0 mmol) and thionyl chloride (3.57 g, 30.0 mmol) at 0° C.The reaction mixture was heated at reflux for 1 h. The reaction mixturewas cooled down to ambient temperature and concentrated under reducedpressure. The residue was dissolved in tetrahydrofuran (100 mL) andacetic acid (10 mL) and zinc dust (6.54 g, 100.0 mmol) were added insmall portions at ambient temperature. The reaction mixture was stirredat ambient temperature for 16 h and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was purified by columnchromatography with a 20% to 80% gradient of ethyl acetate in hexanes toafford1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(1.10 g, 17%) as a colorless solid: MS (ES+) m/z 440.2 (M+1).

C. Synthesis of1′-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A suspended mixture of1-(diphenylmethyl)-3-(4-fluoro-2-hydroxy-5-methoxyphenyl)-1,3-dihydro-2H-indol-2-one(1.10 g, 2.5 mmol), chloroiodomethane (0.70 g, 4.0 mmol) and cesiumcarbonate (2.60 g, 8.0 mmol) in tetrahydrofuran (50 mL) was stirred atambient temperature for 24 h. The reaction mixture was filtered. Thesolid was washed with acetone (50 mL). The filtrate was concentrated invacuo to dryness. The residue was purified by column chromatography witha 20% to 70% gradient of ethyl acetate in hexanes to afford1-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.49 g, 43%) as a colorless solid: MS (ES+) m/z 452.0 (M+1).

D. Synthesis of6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A suspended mixture of1-(diphenylmethyl)-6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.49 g, 1.09 mmol), triethylsilane (0.23 g, 2.0 mmol) andtrifluoroacetic acid (0.57 g, 5.0 mmol) was refluxed under nitrogen for5 h. The reaction mixture was cooled to ambient temperature andconcentrated under reduced pressure. The oily residue was sonicated withhexanes (10 mL) for 10 min and a solid product was filtered off toafford 6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.29 g, 92%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.28 (s,1H), 7.37-6.91 (m, 4H), 6.74 (d, J=11.0 Hz, 1H), 6.39 (d, J=8.3 Hz, 1H),4.82 (ABq, 2H), 3.68 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 180.0, 155.2,154.9, 154.7, 151.9, 142.9, 142.7, 140.2, 132.1, 129.2, 124.1, 123.6,122.7, 122.7, 110.4, 109.0, 108.9, 100.0, 99.7, 80.5, 58.8, 57.2; MS(ES+) m/z 285.8 (M+1).

Preparation 68 Synthesis of1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 26A and makingnon-critical variations using 7-fluoroisatin to replace2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, andbromodiphenylmethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (80%): MS(ES+) m/z 353.7 (M+23).

B. Synthesis of1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

To a cooled (0° C.) suspension of 2,3-dihydro-1,4-benzodioxin-6-ol (0.47g, 3.0 mmol) in anhydrous tetrahydrofuran (12 mL) was addedisopropylmagnesium chloride (2 M solution in tetrahydrofuran, 1.7 mL,3.3 mmol). The reaction mixture was stirred at 0° C. for 1 h, and7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione (1.0 g, 3.0 mmol) andanhydrous dichloromethane (10 mL) were added. The reaction mixture wasallowed to stir for 19 h at ambient temperature. The reaction mixturewas concentrated in vacuo and was diluted with saturated aqueousammonium chloride (30 mL) and ethyl acetate (30 mL). The phases wereseparated and the aqueous phase was extracted with ethyl acetate (2×50mL). The combined organic extracts were washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The crude product was purified by column chromatography and eluted witha 8% to 66% gradient of ethyl acetate in hexanes to afford1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(1.22 g, 84%) as an off-white solid: MS (ES+) m/z 475.0 (M−17).

C. Synthesis of1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-7-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(4.27 g, 8.8 mmol) in trifluoroacetic acid (100 mL) at 0° C. was addedtriethylsilane (2.8 mL, 18 mmol) and the reaction mixture wasconcentrated in vacuo. The crude product was purified by columnchromatography and eluted with a 0% to 66% gradient of ethyl acetate inhexanes to afford1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(2.5 g, 61%) as a colorless solid: MS (ES+) m/z 465.9 (M+1).

Preparation 69 Synthesis of4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of4′-acetyl-1-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.15 g, 0.41 mmol) in anhydrous tetrahydrofuran (5 mL) was addedphenyltrimethylammonium tribromide (0.16 g, 0.41 mmol) and the reactionmixture was stirred at ambient temperature for 1 h. Water (30 mL) wasadded and, after stirring for 5 min, the mixture was partitioned betweenbrine (30 mL) and ethyl acetate (30 mL). The aqueous phase was extractedwith ethyl acetate (2×20 mL) and the combined organic extracts werewashed with brine (20 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to afford a heavy yellow oil. The oil wasdissolved in dichloromethane (4 mL) and diethyl ether (30 mL) was added,causing a precipitate to be deposited. The solid was collected by vacuumfiltration, washed with diethyl ether (10 mL), air-dried and dried underhigh vacuum to afford4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.125 g, 70%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ7.51-7.42 (m, 2H), 7.13-7.08 (m, 1H), 6.49 (s, 1H), 6.02 (s, 1H),4.93-4.78 (m, 2H), 4.22-4.02 (m, 6H), 3.28 (s, 3H); MS (ES+) m/z 429.4(M+1), 431.4 (M+1).

Preparation 70 Synthesis of ethyl3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-3-oxopropanoate

To a suspension of sodium hydride (60% w/w dispersion in mineral oil,0.11 g, 2.8 mmol) in anhydrous tetrahydrofuran (10 mL) at ambienttemperature was added diethyl carbonate (0.26 mL, 2.1 mmol) and themixture was heated at reflux for 5 min.4′-Acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.50 g, 1.4 mmol) was added in one portion and the reaction mixture washeated at reflux for 16 h, allowed to cool to ambient temperature andpoured into water (75 mL). The mixture was extracted withdichloromethane (3×50 mL). The combined organic extracts were washedwith brine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography and eluted with a 0% to 10% gradient of ethyl acetate indichloromethane, followed by recrystallization fromdichloromethane/diethyl ether to afford ethyl3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-3-oxopropanoate(0.235 g, 39%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.50-7.43 (m, 2H), 7.14-7.09 (m, 1H), 6.51 (s, 1H), 6.02 (s, 1H),4.97-4.78 (m, 2H), 4.20-4.03 (m, 6H), 3.89 (d, J=15.6 Hz, 1H), 3.65 (d,J=15.6 Hz, 1H), 3.29 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ES+) m/z 445.8(M+23).

Preparation 71 Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

To a solution of 2,2-difluoro-1,3-benzodioxol-5-ol (Jacobus et al., WO2004/4048320) (1.15 g, 6.60 mmol) in anhydrous tetrahydrofuran at 0° C.was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran,3.3 mL, 6.6 mmol). The reaction mixture was stirred at 0° C. for 0.5 hand 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (1.95g, 6.60 mmol) was added. The reaction mixture was allowed to warm toambient temperature and stirred for 96 h. A saturated aqueous solutionof ammonium chloride (30 mL) was added and the mixture was extractedwith ethyl acetate (3×30 mL). The combined organic extracts were washedwith brine (2×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Purification of the residue by columnchromatography eluted with a 0% to 35% gradient of ethyl acetate inhexanes afforded3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(2.54 g, 73%) as a pale orange solid: MS (ES+) 451.3 (M−17).

B. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

To a solution of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(2.50 g, 5.32 mmol) in anhydrous dichloromethane (10 mL) at 0° C. wasadded triethylsilane (4.2 mL, 26 mmol) and trifluoroacetic acid (12 mL).The reaction mixture was allowed to warm to ambient temperature and wasstirred for 72 h and was concentrated in vacuo. Purification of theresidue by column chromatography and eluted with a 0% to 30% gradient ofethyl acetate in hexanes afforded3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(1.81 g, 75%) as a colorless amorphous solid: MS (ES+) m/z 454.2 (M+1).

Preparation 72 Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-methyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(methoxymethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 71A and makingnon-critical variations using 1-(methoxymethyl)-1H-indole-2,3-dione(Trost and Frederiksen, Angew. Chem. Intl. Ed. Engl. 2005,44(2):308-310) to replace1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione,3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(methoxymethyl)-1,3-dihydro-2H-indol-2-onewas obtained (48%) as a tan amorphous solid: ¹H NMR (300 MHz, CDCl₃)δ9.20 (br s, 1H), 7.50-7.40 (m, 2H), 7.29-7.21 (m, 1H), 7.13 (d, J=7.7Hz, 1H), 6.77 (s, 1H), 6.53 (s, 1H), 4.45 (br s, 1H), 5.15-5.04 (m, 2H),3.30 (s, 3H).

B. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-methyl-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 71B and makingnon-critical variations using3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-(methoxymethyl)-1,3-dihydro-2H-indol-2-oneto replace3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one,3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-methyl-1,3-dihydro-2H-indol-2-onewas obtained (85%) as a colorless amorphous solid: ¹H NMR (300 MHz,CDCl₃) δ7.47-7.40 (m, 1H), 7.37-7.31 (m, 1H), 7.28-7.20 (m, 2H), 6.99(d, J=7.8 Hz, 1H), 6.85 (s, 1H), 6.60 (s, 1H), 5.10 (s, 1H), 3.25 (s,3H); MS (ES+) m/z 320.1 (M+1).

Preparation 73 Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indole-2,3-dione

To a cooled (0° C.) solution of 1H-indole-2,3-dione (2.08 g, 14.1 mmol)in anhydrous N,N-dimethylformamide (40 mL) was added sodium hydride (60%dispersion in mineral oil, 1.18 g, 29.6 mmol) and the resultant purplesuspension was stirred at 0° C. for 15 min. To the aforementionedsuspension was added, via cannula over a period of 10 min, a solution of2-(chloromethyl)-6-(trifluoromethyl)pyridine hydrochloride (Li, J. WO2006/34004) (3.27 g, 14.1 mmol) in anhydrous N,N-dimethylformamide (20mL). The reaction mixture was allowed to warm to ambient temperature,stirred for 2.5 h and poured into a cooled (0° C.), well-stirred mixtureof brine (60 mL) and water (60 mL). The resultant orange suspension wassonicated for 5 min, allowed to warm to ambient temperature andfiltered. The filter cake was washed with water (100 mL) and hexanes(100 mL), air-dried and dried under high vacuum to afford1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indole-2,3-dione (3.21 g,74%) as an orange solid: ¹H NMR (300 MHz, CDCl₃) δ8.59 (d, J=4.8 Hz,1H), 8.00 (d, J=7.9 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.49-7.42 (m, 1H),7.37-7.30 (m, 1H), 7.12-7.06 (m, 1H), 6.59 (d, J=7.9 Hz, 1H), 5.24 (s,2H); MS (ES+) m/z 307.3 (M+1).

B. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure described in PREPARATION 71A and makingnon-critical variations using1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indole-2,3-dione toreplace 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione,3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (32%) as a tan amorphous solid: MS (ES+) m/z 481.2 (M+1).

C. Synthesis of3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure described in PREPARATION 71B and makingnon-critical variations using3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneto replace3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one,3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (91%) as a colorless amorphous solid: MS (ES+) m/z 465.2(M+1).

Preparation 74 Synthesis of6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneA. Synthesis of6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione

To a cooled (0° C.) solution of2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey andSternbach, Synthesis 1993:993-997) (1.73 g, 8.42 mmol) in anhydrousN,N-dimethylformamide (28 mL) was added sodium hydride (60% in mineraloil, 0.37 g, 9.26 mmol). The mixture was stirred at ambient temperaturefor 1 h and bromodiphenylmethane (2.39 g, 9.69 mmol) was added. Afterstirring at ambient temperature for 16 h, further bromodiphenylmethane(0.42 g, 1.68 mmol) was added. The mixture was stirred at ambienttemperature for 8 h and then diluted with water (200 mL) and ethylacetate (200 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (150 mL), dried over anhydrous magnesium sulfate,filtered, concentrated in vacuo. The residue was purified by columnchromatography, eluted with a 35% to 50% gradient of ethyl acetate inhexanes to afford6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione(0.7 g, 22%) as a red solid: ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.28 (m,10H), 7.16 (s, 1H), 6.94-6.91 (m, 1H), 5.96 (s, 1H), 4.27-4.14 (m, 4H);MS (ES+) m/z 371.9 (M+1).

B. Synthesis of6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3-bromophenol, and6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione toreplace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained (94%) as a colorless solid: MS (ES−) m/z 506.1 (M−1).

C. Synthesis of6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

A mixture of6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one(0.78 g, 1.5 mmol), triethylsilane (1.2 mL) and trifluoroacetic acid(1.2 mL) in dichloromethane (10 mL) was stirred at 0° C. for 1 h andthen at ambient temperature for 1 h. The mixture was concentrated invacuo to afford crude6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one(100%): MS (ES+) m/z 492.1 (M+1).

Preparation 75 Synthesis of1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-oneA. Synthesis of3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione

To a stirred solution of 1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione(Bramson, H. N. et al. J. Med. Chem. 2001, 44 (25):4339-4358) (0.15 g,0.76 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride(60% in mineral oil, 0.04 g, 0.98 mmol) at ambient temperature. Themixture was stirred at ambient temperature for 1 h and 4-methoxybenzylbromide (0.16 mL, 1.1 mmol) was added. The mixture was stirred atambient temperature for 16 h and was diluted with water (100 mL) andethyl acetate (100 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (50 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography eluted with a 50% to 65% gradient of ethyl acetate inhexanes to afford3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione (0.20 g,82%) as a red solid: MS (ES+) m/z 319.0 (M+1).

C. Synthesis of1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzofuran-6-ol to replace3-bromophenol, and3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-onewas obtained (58%) as a colorless solid: MS (ES+) m/z 455.0 (M+1).

D. Synthesis of1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one

Following the procedure as described in PREPARATION 74C and makingnon-critical variations using1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-oneto replace6-(diphenylmethyl)-8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one,1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-onewas obtained (37%) as a colorless solid: MS (ES+) m/z 438.9 (M+1).

Preparation 76 Synthesis of2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrileA. Synthesis of2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile

To a stirred solution of 2,4-dihydroxybenzonitrile (4.33 g, 32.1 mmol)in tetrahydrofuran (50 mL) and 1,2-dichloroethane (400 mL) was addedisopropylmagnesium chloride (17.7 mL, 2.0 M solution in tetrahydrofuran,35.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and atambient temperature for 2 h, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione(8.58 g, 32.1 mmol) was added to the reaction mixture. The mixture wasstirred at reflux for 18 h, cooled to 0° C. and 5% v/v hydrochloric acidwas added. The organic layer was separated and washed with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography and eluted with ethyl acetate/hexanes (1/1) to afford2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(10.30 g, 79%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.81 (s, 1H), 10.35 (s,1H), 7.80 (s, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.14-7.08 (m, 1H), 6.88-6.84(m, 4H), 6.75-6.72 (m, 1H), 6.63 (s, 1H), 6.30 (s, 1H), 4.79 (ABq, 2H),3.70 (s, 3H); MS (ES+) m/z 384.8 (M−17).

B. Synthesis of2,4-dihydroxy-5-[1′-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile

To a stirred suspension of2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(10.3 g, 25.5 mmol) and triethylsilane (12.3 mL, 77.0 mmol) indichloromethane (100 mL) was added trifluoroacetic acid (10.0 mL, 129mmol). The reaction mixture was stirred at ambient temperature for 18 hand concentrated in vacuo. The residue was triturated in hexanes toafford2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(9.70 g, 98%): mp 162-163° C. (hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.84(s, 1H), 10.47 (s, 1H), 7.39 (s, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.13-7.08(m, 1H), 6.93-6.78 (m, 5H), 6.43 (s, 1H), 5.72 (s, 1H), 4.92-4.73 (m,3H), 3.69 (s, 3H); MS (ES+) m/z 386.9 (M+1).

Preparation 77 Synthesis of2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrileA. Synthesis of2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile

To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (8.00 g, 58.3mmol) in 1,2-dichloroethane (500 mL) and tetrahydrofuran (50 mL) wasadded isopropylmagnesium chloride (29.2 mL, 2.0 M solution intetrahydrofuran, 58.4 mmol) at 0° C. The mixture was stirred at 0° C.for 1 h and at ambient temperature for 2 h.1-(4-methoxybenzyl)-1H-indole-2,3-dione (15.0 g, 56.1 mmol) was addedand the reaction mixture was stirred at reflux for 156 h. The mixturewas cooled to 0° C. and 10% w/v hydrochloric acid was added. The phaseswere separated and the aqueous layer was extracted with dichloromethane(100 mL). The combined organic extracts were washed with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography and eluted with ethyl acetate/hexanes (1/1) to afford2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(12.30 g, 54%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=9.0 Hz, 1H),7.34-7.32 (m, 2H), 7.17-7.11 (m, 1H), 6.91-6.76 (m, 7H), 4.78 (ABq, 2H),3.72 (s, 3H); MS (ES+) m/z 404.9 (M+1).

B. Synthesis of2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile

To a stirred suspension of2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(12.0 g, 29.7 mmol) in triethylsilane (14.2 mL, 88.9 mmol) was addedtrifluoroacetic acid (10.0 mL, 129 mmol). The reaction mixture wasstirred at ambient temperature for 168 h and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate/hexanes to afford2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(10.5 g, 90%): ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.12 (m, 7H), 6.94 (d,J=6.0 Hz, 1H), 6.85-6.79 (m, 3H), 5.07 (s, 1H), 4.88 (ABq, 2H), 3.75 (s,3H); MS (ES+) m/z 388.9 (M+1).

Preparation 78 Synthesis of3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of 3-methyl-1,2-benzisoxazol-5-ol (Lindemann, etal Justus Liebigs Annalen der Chemie 1927, 456:308) (3.10 g, 20.8 mmol)in 1,2-dichloroethane (200 mL) was added isopropylmagnesium chloride(10.4 mL, 2.0 M solution in tetrahydrofuran, 20.8 mmol) at 0° C. Themixture was stirred at 0° C. for 1 h and then at ambient temperature for2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (5.3 g, 19.8 mmol) wasadded and the reaction mixture was stirred at reflux for 120 h. Themixture was cooled to 0° C. and 5% w/v hydrochloric acid was added. Theorganic phase was separated, washed with water and brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo. The residue was subjected to column chromatography eluted withethyl acetate/hexanes (1/1) to afford3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one(0.87 g, 10%): ¹H NMR (300 MHz, DMSO-d₆) δ 9.68 (s, 1H), 8.01 (s, 1H),7.37-6.76 (m, 10H), 4.83 (ABq, 2H), 3.70 (s, 3H), 2.46 (s, 3H); MS (ES+)m/z 415.0 (M−1).

B. Synthesis of3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one

To a stirred suspension of3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one(0.84 g; 2.0 mmol) in triethylsilane (3.0 mL, 18.7 mmol) was addedtrifluoroacetic acid (15.0 mL). The reaction mixture was stirred at 50°C. for 26 h, allowed to cool to ambient temperature and concentrated invacuo. The residue was recrystallized from ethyl acetate/hexanes toafford3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one(0.74 g, 92%): ¹H NMR (300 MHz, CDCl₃) δ 7.34-6.80 (m, 10H), 5.29 (s,1H), 4.87 (ABq, 2H), 3.74 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 400.9(M+1).

Preparation 79 Synthesis of4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4-bromo-1-methyl-1H-indole-2,3-dione

To a stirred solution of 4-bromoisatin (90.4 g, 400 mmol) inN,N-dimethylformamide (400 mL) was added cesium carbonate (196.0 g, 600mol) at ambient temperature. The reaction mixture was stirred for 30min, iodomethane (37.4 mL, 600 mmol) was added and the mixture wasstirred at ambient temperature for 18 h. The solid was removed byfiltration, the filtrate was concentrated in vacuo, and the residue wastriturated in water and washed with diethyl ether to afford4-bromo-1-methyl-1H-indole-2,3-dione (82.0 g, 85%): ¹H NMR (300 MHz,DMSO-d₆) δ 7.95-7.89 (m, 1H), 7.68-7.64 (m, 1H), 7.53-7.49 (m, 1H), 3.50(s, 3H).

B. Synthesis of4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one

To a stirred solution of 2,3-dihydro-1,4-benzodioxin-6-ol (36.0 g, 230mmol) in dichloromethane (1000 mL) was added isopropylmagnesium chloride(120 mL, 2.0 M solution in tetrahydrofuran, 240 mmol) at 0° C. Themixture was allowed to stir at 0° C. for 1 h and4-bromo-1-methyl-1H-indole-2,3-dione (48.0 g, 200 mmol) was added. Thereaction mixture was stirred at ambient temperature for 22 h and 5% w/vhydrochloric acid was added at 0° C. The organic layer was separated,washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo and the residue wastriturated in methanol and washed with diethyl ether to afford4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one(63.4 g, 80%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.80 (s, 1H), 7.21-7.13 (m,2H), 7.01-6.93 (m, 2H), 6.45 (s, 1H), 6.03 (s, 1H), 4.17-4.10 (m, 4H),3.08 (s, 3H); MS (ES+) m/z 373.8 (M−17), 375.8 (M−17).

C. Synthesis of4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one

To a stirred solution of4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one(61.0 g; 155 mmol) and triethylsilane (75.0 mL, 456 mmol) indichloromethane (300 mL) was added trifluoroacetic acid (48 mL, 623mmol) at 0° C. The reaction mixture was stirred at ambient temperaturefor 20 h and concentrated in vacuo. The residue was triturated inmethanol and washed with diethyl ether to afford4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one(57.0 g, 97%): ¹H NMR (300 MHz, CDCl₃)

7.31-7.17 (m, 3H), 6.87-6.83 (m, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 4.97(s, 1H), 4.22-4.08 (m, 4H), 3.18 (s, 3H); MS (ES+) m/z 376.1 (M+1),378.1 (M+1).

Preparation 80 Synthesis of methyl6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylateA. Synthesis of6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione

Following the procedure as described in PREPARATION 79A, and makingnon-critical variations using2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace4-bromoisatin,6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione was obtained(68%): ¹H NMR (300 MHz, CDCl₃) δ 7.09 (s, 1H), 6.74 (s, 1H), 4.41-4.38(m, 2H), 4.27-4.24 (m, 2H), 3.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)₈; MS(ES+) m/z 220.2 (M+1).

B. Synthesis of6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

To a solution of6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (3.00 g,13.7 mmol) in 1,4-dioxane (25 mL) was added hydrazine monohydrate (25mL). The reaction mixture was stirred at reflux for 4 h, allowed to coolto ambient temperature, diluted with ethyl acetate, washed with waterand brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was recrystallized fromethyl acetate/hexanes to afford6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (2.46 g,87%): ¹H NMR (300 MHz, CDCl₃) δ 6.75 (s, 1H), 6.49 (s, 1H), 4.19-4.12(m, 4H), 3.36 (s, 2H), 3.00 (s, 3H); MS (ES+) m/z 206.2 (M+1).

C. Synthesis of6-methyl-8-(2-nitrophenyl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

To a stirred solution of6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (1.03 g,5.01 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride(60% w/w dispersion in mineral oil, 0.26 g, 6.5 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 30 min,1-fluoro-2-nitrobenzene (0.70 mL, 6.6 mmol) was added and the mixturewas stirred at ambient temperature for 18 h, 10% w/v hydrochloric acid(10 mL) was added at 0° C. and the mixture was extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with waterand brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography and eluted with ethyl acetate/hexanes (1/2) to afford6-methyl-8-(2-nitrophenyl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one(0.41 g, 24%): ¹H NMR (300 MHz, CDCl₃) δ 8.05-8.01 (m, 1H), 7.58-7.51(m, 1H), 7.49-7.42 (m, 1H), 7.23-7.19 (m, 1H), 6.69 (s, 1H), 6.45 (s,1H), 5.28 (s, 1H), 4.28-4.18 (m, 4H), 3.21 (s, 3H).

D. Synthesis of methyl6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylate

To a stirred solution of6-methyl-8-(2-nitrophenyl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one(0.40 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added lithiumbis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 1.5 mL, 1.5mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min,methyl cyanoformate (0.12 mL, 1.5 mmol) was added and the mixture wasstirred at ambient temperature for 18 h. 10% w/v hydrochloric acid (5mL) was added at 0° C. and the mixture was extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was purified by columnchromatography and eluted with ethyl acetate/hexanes (1/2) to affordmethyl6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylate(0.21 g, 44%): ¹H NMR (300 MHz, CDCl₃) δ 7.92-7.89 (m, 1H), 7.48-7.37(m, 2H), 7.20-7.19 (m, 1H), 6.97 (s, 1H), 6.41 (s, 1H), 4.21-4.14 (m,4H), 3.65 (s, 3H), 3.12 (s, 3H).

Preparation 81 Synthesis of4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 4-bromo-benzhydrylindoline-2,3-dione

Following the procedure as described in PREPARATION 26A and makingnon-critical variations using 4-bromoisatin to replace2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, andbromodiphenylmethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,4-bromo-benzhydrylindoline-2,3-dione was obtained (78%) as a red solid:MS (ES+) m/z 413.8 (M+23), 415.8 (M+23).

B. Synthesis of4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydro-1,4-benzodioxin-6-ol toreplace 3-bromophenol, and 4-bromo-1-benzhydrylindoline-2,3-dione toreplace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (99%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.06(s, 1H), 7.44-7.28 (m, 10H), 6.98-6.82 (m, 2H), 6.68 (s, 1H), 6.33 (d,J=7.4 Hz, 1H), 6.16 (s, 1H), 4.23-4.08 (m, 4H); MS (ES+) m/z 566.1(M+23), 568.1 (M+23).

C. Synthesis of4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (86%): as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.05(s, 1H), 7.42-7.28 (m, 10H), 6.98-6.87 (m, 3H), 6.68 (s, 1H), 6.33 (d,J=7.6 Hz, 1H), 6.16 (s, 1H), 4.22-4.16 (m, 4H).

Preparation 82 Synthesis of1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione

To a solution of 1-(diphenylmethyl)-3-iodo-4-fluoroindole (8.85 g, 20.7mmol) in a mixture of acetonitrile (25 mL) and water (5 mL) was addedruthenium (III) chloride monohydrate (0.30 g, 1.45 mmol) and sodiumperiodate (13.3 g, 62.2 mmol). The reaction mixture was stirred atambient temperature for 16 h. The reaction mixture was diluted withethyl acetate (100 mL), washed with water (3×25 mL), saturated aqueousammonium chloride (3×25 mL) and brine (3×25 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue wascrystallized from acetonitrile to afford1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione (1.73 g, 25%) as anorange solid: mp 168-171° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.49-7.41 (m,1H), 7.38-7.28 (m, 10H), 6.86 (dd, J=8.8, 8.8 Hz, 1H), 6.80 (s, 1H),6.45 (d, J=8.1 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.3, 157.8, 157.7(d, 1J_(C-F)=261.0 Hz), 150.6 (d, ³J_(C-F)=6.0 Hz), 139.7 (d,2J_(C-F)=10.0 Hz), 137.0, 128.5, 128.3, 127.8, 110.7 (d, ²J_(C-F)=19.5Hz), 108.8 (d, ⁴J_(C-F)=2.9 Hz), 106.4 (d, ³J_(C-F)=18.2 Hz), 28.7; MS(ES+) m/z 332.2 (M+23).

B. Synthesis of1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 2-methylbenzo[d]thiazol-5-ol, and1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione to replace isatin,1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (83%) as a colourless solid: mp 209-211° C. (dec.); ¹H NMR(300 MHz, DMSO-d₆) δ 9.15 (s, 1H), 7.43-7.27 (m, 11H), 7.01 (ddd, J=8.2,8.2, 5.9 Hz, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.61 (dd, J=8.8, 8.8 Hz,1H), 6.21 (s, 1H), 6.16 (d, J=7.9 Hz, 1H), 4.25-4.14 (m, 4H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.2, 157.9 (d, ¹J=248 Hz), 147.1, 145.0 (d,³J_(C-F)=8.7 Hz), 142.7, 137.7 (d, 2J_(C-F)=30.9 Hz), 135.4, 130.1 (d,³J_(C-F)=8.7 Hz), 128.4 (d, ³J_(C-F)=13.9 Hz), 128.3 (d, ³J_(C-F)=8.4Hz), 127.5 (d, ³J_(C-F)=11.9 Hz), 119.4, 117.9 (d, ²J_(C-F)=18.9 Hz),116.1, 109.3 (d, ²J_(C-F)=20.3 Hz), 107.2 (d, ⁴J_(C-F)=2.1 Hz), 103.1,73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 506.0 (M+23).

C. Synthesis of1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

To a solution of1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(1.74 g, 3.60 mmol) in dichloromethane (40 mL) was added trifluoroaceticacid (1.64 g, 14.4 mmol) and triethylsilane (1.68 g, 14.4 mL). Thereaction mixture was stirred at ambient temperature for 16 h andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a gradient of ethyl acetate in hexanes to afford1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(1.54 g, 92%) as a colourless solid: mp 115-118° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.17 (s, 1H), 7.42-7.26 (m, 11H), 7.01 (ddd, J=8.2, 8.2, 5.9Hz, 1H), 6.91 (s, 1H), 6.67 (dd, J=8.8, 8.8 Hz, 1H), 6.27 (s, 1H), 6.23(d, J=7.9 Hz, 1H), 4.99 (s, 1H), 4.20-4.14 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.2, 157.9 (d, ¹J_(C-F)=248 Hz), 147.1, 145.0 (d,³J_(C-F)=8.7 Hz), 142.7, 137.7 (d, ²J_(C-F)=30.9 Hz), 135.4, 130.1 (d,³J_(C-F)=8.7 Hz), 128.4 (d, ³J_(C-F)=13.9 Hz), 128.3 (d, ³J_(C-F)=8.4Hz), 127.5 (d, ³J_(C-F)=11.9 Hz), 119.4, 117.9 (d, ²J_(C-F)=18.9 Hz),116.1, 109.3 (d, ²J_(C-F)=20.3 Hz), 107.2 (d, ⁴J_(C-F)=2.1 Hz), 103.1,73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 467.9 (M+1)

Preparation 83 Synthesis of1-(4-fluorophenyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 1A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 2-methylbenzo[d]thiazol-5-ol, and1-(4-fluorophenyl)indoline-2,3-dione (Coppola, G. M Journal ofHeterocyclic Chemistry 1987, (24):1249) to replace isatin,1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (23%) as a beige solid: mp 195-200° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.12 (s, 1H), 7.47-7.41 (m, 4H), 7.26 (s, 1H), 7.21-7.16 (m,1H), 7.01-6.93 (m, 2H), 6.68 (d, J=7.8 Hz, 1H), 6.63 (s, 1H), 6.14 (s,1H), 4.23-4.14 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 160.9 (d,¹J_(C-F)=245 Hz), 147.1, 143.9, 142.6, 135.6, 132.0, 131.2 (d,⁴J_(C-F)=2.9 Hz), 128.6 (d, ³J_(C-F)=8 Hz), 124.0, 122.4, 121.2, 116.4(d, ²J_(C-F)=22.8 Hz), 115.1, 108.2, 103.4, 74.4, 64.3, 63.7, 57.2; MS(ES+) m/z 390.0 (M+1).

B. Synthesis of1-(4-Fluorophenyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 82C and makingnon-critical variations using1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one,1-(4-fluorophenyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (59%) as a colourless solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.16 (s, 1H), 7.51-7.39 (m, 4H), 7.17 (dd, J=7.6 Hz, 7.6 Hz, 1H),7.05-6.96 (m, 2H), 6.67 (s, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.27 (s, 1H),4.84 (s, 1H), 4.19-4.12 (m, 4H): MS (ES+) m/z 378.2 (M+1).

Preparation 84 Synthesis of 4-(chloromethyl)-1-fluoro-2-methoxybenzene

To a solution of (4-fluoro-3-methoxyphenyl)methanol (Claudi, et al., J.Med. Chem. 1990, 33(9):2408) (0.90 g, 5.76 mmol) in anhydrousdichloromethane (10 mL) was added thionyl chloride (0.84 mL, 12 mmol)and anhydrous N,N-dimethylformamide (2 drops). The reaction mixture wasstirred at ambient temperature for 16 h and concentrated in vacuo toafford 4-(chloromethyl)-1-fluoro-2-methoxybenzene (0.73 g, 72%) as abrown oil: ¹H NMR (300 MHz, CDCl₃) δ 7.05-6.86 (m, 3H), 4.53 (s, 2H),3.88 (s, 3H).

Preparation 85 Synthesis of 2-(chloromethyl)-3,5-difluoropyridinehydrochloride

To a solution of (3,5-difluoropyridin-2-yl)methanol (Almedia et al., WO08/117,050) (2.15 g, 14.8 mmol) in dichloromethane (20 mL) at 0° C. wasadded N,N-dimethylformamide (2 drops) and thionyl chloride (2.0 mL, 27mmol). The solution was stirred at ambient temperature for 1 h andconcentrated in vacuo to afford 2-(chloromethyl)-3,5-difluoropyridinehydrochloride (2.31 g, 78%) as a brown oil: Rf=0.71 (EtOAc/Hexanes,1/1).

Preparation 86 Synthesis of 2-(chloromethyl)-4-fluoropyridinehydrochloride

To a solution of methyl 4-fluoropicolinate (0.50 g, 3.20 mmol) intetrahydrofuran (20 mL) at −78° C. was added slowly lithium aluminumhydride (0.15 g, 4.00 mmol). The solution was stirred at −78° C. for 2 hand water (1 mL) was added. The reaction mixture was allowed to warm toambient temperature, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford (4-fluoropyridin-2-yl)methanol as a paleyellow oil. To a solution of this oil in dichloromethane (10 mL) wasadded thionyl chloride (1.0 mL, 13 mmol) and the solution was stirred atambient temperature for 16 h. The solution was concentrated in vacuo toafford 2-(chloromethyl)-4-fluoropyridine hydrochloride (0.42 g, 71%) asa beige solid: ¹H NMR (300 MHz, CDCl₃) δ 8.53-8.47 (m, 1H), 7.04-6.90(m, 2H), 4.74 (s, 2H).

Preparation 87 Synthesis of5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione

To a solution of 5-bromoisatin (10.0 g, 44.4 mmol) in anhydrousN,N-dimethylformamide (100 mL) at 0° C. was added slowly sodium hydride(60% w/w dispersion in mineral oil, 3.90 g, 97.7 mmol). The solution wasstirred for 30 min and 2-(bromomethyl)pyridine hydrobromide (11.2 g,44.4 mmol) was added. The solution was stirred at ambient temperaturefor 16 h and poured into ice water (1.3 L) with vigourous stirring,causing a precipitate to be deposited. The solid was collected byfiltration to afford 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione(4.93 g, 35%) as a orange solid: ¹H NMR (300 MHz, CDCl₃)

8.55-8.50 (m, 1H), 7.72-7.56 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.18 (m,1H), 6.93-6.88 (m, 1H), 5.03-4.99 (m, 2H).

B. Synthesis of5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one

To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.55 g, 16.8 mmol)in anhydrous dichloromethane (100 mL) at 0° C. added isopropylmagnesiumchloride (2 M solution in tetrahydrofuran, 10.0 mL, 19.9 mmol). Thesolution was stirred at 0° C. for 20 min and5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.85 g, 15.3 mmol)was added. The reaction mixture was stirred at ambient temperature for16 h, saturated aqueous ammonium chloride (25 mL) was added and themixture was concentrated in vacuo. The residue was triturated with ethylacetate (250 mL) and the solid collected by filtration to afford5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(7.26 g, 98%) as a beige solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.20 (s,1H), 8.71 (d, J=4.9 Hz, 1H), 8.06 (dd, J=7.80 Hz, 1H), 7.63-7.55 (m,2H), 7.52 (d, J=8.0 Hz, 1H), 7.35 (dd, J=8.3, 2.0 Hz, 1H), 7.20 (s, 1H),6.99 (d, J=2.0 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.16 (s, 2H), 5.09 (ABq,2H), 4.20-4.10 (m, 4H).

C. Synthesis of5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one

To a suspension of5-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(3.60 g, 8.10 mmol) in triethylsilane (10 mL) at 0° C. was addedtrifluoroacetic acid (40 mL). The solution was allowed to warm toambient temperature over 2 h and was stirred for a further 4 h. Thereaction mixture was concentrated in vacuo and saturated aqueous sodiumbicarbonate and ethyl acetate were added to the residue, causing aprecipitate to be deposited. The solid was collected by filtration andwashed sequentially with diethyl ether and hexanes to afford5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(4.03 g, 100%) as a pale yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.59-8.55 (m, 1H), 7.90-7.80 (m, 1H), 7.44-7.37 (m, 1H), 7.34-7.27 (m,1H), 7.07 (s, 1H), 6.82-6.68 (m, 2H), 6.27 (s, 1H), 5.17-4.93 (m, 2H),4.84 (s, 1H), 4.23-4.06 (m, 4H). MS (ES+) m/z 452.9 (M+1), 454.9 (M+1).

Preparation 88 Synthesis of5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 5-bromo-1-(diphenylmethyl)-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 26A and makingnon-critical variations using 5-bromoisatin to replace2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, andbromodiphenylmethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5-bromo-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (76%): ¹HNMR (300 MHz, CDCl₃) δ 7.74-7.67 (m, 1H), 7.46-7.20 (m, 11H), 6.96 (s,1H), 6.37 (d, J=8.5 Hz, 1H).

B. Synthesis of5-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 87B and makingnon-critical variations using5-bromo-1-(diphenylmethyl)-1H-indole-2,3-dione to replace5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione,5-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (64%) as a pale yellow solid: MS (ES+) m/z 525.9 (M−17),527.9 (M−17).

C. Synthesis of5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 82C and makingnon-critical variations using5-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one,5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (85%) as a colorless solid: MS (ES+) m/z 527.8 (M+1), 529.8(M+1).

Preparation 89 Synthesis of1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine

A solution of 5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (1.54 g, 10.0mmol) and 1-bromopyrrolidine-2,5-dione (1.8 g, 10 mmol) in methanol (20mL) was heated at reflux for 0.5 h, allowed to cool to ambienttemperature and concentrated in vacuo. The residue was taken up indichloromethane (50 mL) and washed with water (50 mL). The organic phasewas dried over magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography eluted with a 0% to30% gradient of ethyl acetate in hexanes afforded7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (2.04 g, 87%) as acolorless solid: MS (ES+) m/z 233.6 (M+1).

B. Synthesis of 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

To a solution of 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (15.1g, 64.8 mmol) in tetrahydrofuran (160 mL) at −78° C. was added a 1.6 Msolution of n-butyllithium in hexanes (45 mL, 73 mmol). The reactionmixture was stirred at −78° C. for 15 min and trimethyl borate (8.5 g,82 mmol) was added. The reaction mixture was allowed to warm to ambienttemperature, stirred for 48 h and cooled to 5° C. 35% w/w aqueoushydrogen peroxide (12.6 mL, 129.6 mmol) was added, the reaction mixturewas allowed to warm to ambient temperature and stirred for 3 h. Thereaction mixture was diluted with ethyl acetate (200 mL) and the organicphase was washed with 1 M hydrochloric acid (50 mL) and brine (50 mL),dried over magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography eluted with a 0% to70% gradient of ethyl acetate in hexanes afforded8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.5 g, 59%) as a colorlesssolid: MS (ES+) m/z 153.0 (M−17).

C. Synthesis of1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

A 100 mL round-bottom flask was charged with8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.4 g, 37 mmol) andtetrahydrofuran (60 mL). A 2 M solution of isopropylmagnesium chloridein tetrahydrofuran (20.0 mL, 40.0 mmol) was added at 5° C. and thereaction mixture was stirred for 15 min. The reaction mixture wasconcentrated in vacuo and dichloromethane (60 mL) was added, followed bya solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (10.9 g, 35.0 mmol)in dichloromethane (60 mL). The reaction mixture was heated at refluxfor 5 h, allowed to cool to ambient temperature and stirred for afurther 16 h. Saturated aqueous ammonium chloride (30 mL) was added andthe phases were separated. The organic phase was dried over magnesiumsulfate, filtered and concentrated in vacuo.

Trituration of the residue in methanol (30 mL) afforded1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one(10.8 g, 64%) as an off-white solid: MS (ES+) m/z 506.0 (M+23).

D. Synthesis of1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 82C and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (85%) as an off-white solid: MS (ES+) m/z 467.9 (M+1).

Preparation 90 Synthesis of1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one

A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesiumchloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. andthe reaction mixture was stirred for 15 min and concentrated in vacuo.To the residue was added dichloromethane (180 mL), followed by asolution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol)in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed towarm to ambient temperature and stirred for 24 h. Saturated aqueousammonium chloride (7 mL) was added and the reaction mixture wasconcentrated in vacuo. Trituration of the residue in methanol/water(1/100, 200 mL) afforded1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one.A mixture of the1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one,triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438mmol) and dichloromethane (200 mL) was stirred at ambient temperaturefor 20 h and concentrated in vacuo. Trituration of the residue indiethyl ether (150 mL) afforded1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one(24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).

Preparation 91 Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophene-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophene-6-yl)-1,3-dihydro-2H-indol-2-one

To a solution of benzo[b]thiophen-5-ol (1.39 g, 9.25 mmol) intetrahydrofuran (50 mL) at 5° C. was added a 2 M solution ofisopropylmagnesium chloride in tetrahydrofuran (5.0 mL, 10 mmol). Thereaction mixture was stirred at 5° C. for 15 min and concentrated invacuo. To the residue were added 1,2-dichloroethane (100 mL) and1-(diphenylmethyl)-1H-indole-2,3-dione (2.5 g, 8.0 mmol). The reactionmixture was heated at reflux for 3 h, allowed to cool to ambienttemperature and stirred for 48 h. Saturated aqueous ammonium chloride(10 mL) was added and the phases were separated. The organic phase wasdried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography and eluted with a 0% to20% gradient of ethyl acetate in dichloromethane to afford1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one(2.2 g, 59%) as an off-white solid: MS (ES+) m/z 486.0 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 82C and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (94%) as an off-white solid: MS (ES+) m/z 448.1 (M+1).

Preparation 92 Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,1,3-benzoxadiazol-5-ol to replace3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-onewas obtained (71%) as a colorless solid: MS (ES+) m/z 472.0 (M+23).

B. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one

A mixture of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one(21.8 g, 48.5 mmol), triethylsilane (50 mL) and trifluoroacetic acid(100.mL) was stirred at ambient temperature for 16 h, then heated to 45°C. for 1.5 h. The mixture was allowed to cool to ambient temperature andconcentrated in vacuo. The residue was triturated with diethyl ether toafford1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one(10.94 g, 52%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ10.90-10.00 (br s, 1H), 7.61-7.31 (m, 10H), 7.18 (s, 1H), 7.06-6.89 (m,4H), 6.55 (d, J=8.4 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 5.57 (s, 1H); MS(ES+) m/z 456.0 (M+23).

Preparation 93 Synthesis of3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

To a solution of 6-hydroxy-1,4-benzodioxane (1.52 g, 10 mmol) inN,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.33 g, 10mmol) at ambient temperature. The solution was stirred at ambienttemperature for 16 h and concentrated in vacuo. The residue was purifiedby column chromatography and eluted with a 15% to 30% gradient of ethylacetate in hexanes to afford7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (1.79 g, 96%) as acolorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.02 (s, 1H), 6.83 (s, 1H),6.56 (s, 1H), 4.27-4.16 (m, 4H).

B. Synthesis of3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3-bromophenol,and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (18%) as a colorless solid: MS (ES+) m/z 522.1 (M+23),524.1 (M+23).

C. Synthesis of3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations using3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one,3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-onewas obtained (74%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.44-7.27 (m, 10H), 7.08-6.78 (m, 4H), 6.49-6.42 (m, 1H), 5.76 (s,0.5H), 5.30 (s, 0.5H), 5.27 (s, 0.5H), 5.03 (s, 0.5H), 4.39-4.25 (m,2H), 4.06-3.90 (m, 1H), 3.75-3.50 (m, 1H); MS (ES+) m/z 484.3 (M+1),486.3 (M+1).

Preparation 94 Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 3,4-difluorophenol to replace3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methylindoline-2,3-dione,3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.23(br s, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H),6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz,1H), 6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).

B. Synthesis of3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations using3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one,3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-onewas obtained (56%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ9.27(br s, 1H), 7.37-7.12 (m, 12H), 6.94 (s, 1H), 6.87 (dd, J=11.3, 7.1 Hz,1H), 6.76 (dd, J=11.2, 8.9 Hz, 1H), 6.58-6.56 (m, 1H), 5.12 (s, 1H); MS(ES+) m/z 428.2 (M+1).

Preparation 95 Synthesis of1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 5,6,7,8-tetrahydro-2-naphthol to replace3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-onewas obtained (76%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.73(s, 1H), 7.52-7.49 (m, 1H), 7.32-7.28 (m, 10H), 7.09 (dd, J=5.6, 3.2 Hz,2H), 6.95 (s, 1H), 6.75 (s, 1H), 6.51-6.48 (m, 2H), 4.31 (s, 1H), 2.70(br s, 2H), 2.52 (br s, 2H), 1.72 (br s, 4H); MS (ES+) m/z 444.1 (M−17).

B. Synthesis of1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2B, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-oneto replace3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-onewas obtained (71%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.41(s, 1H), 7.33-7.29 (m, 9H), 7.24-7.22 (m, 2H), 7.10-7.07 (m, 2H), 6.98(s, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 6.56-6.53 (m, 1H), 5.13 (s, 1H),2.73 (br s, 2H), 2.60-2.56 (m, 2H), 1.74 (br s, 4H); MS (ES+) m/z 446.0(M+1).

Preparation 96 Synthesis of3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneA. Synthesis of4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 26A and makingnon-critical variations using 4,5-dimethoxyindolin-2,3-dione to replace2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione,4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dionewas obtained (51%) as a red solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.22 (d,J=8.5 Hz, 1H), 7.17-7.12 (m, 1H), 6.77-6.70 (m, 2H), 4.94 (s, 2H), 3.96(s, 3H), 3.72 (s, 3H).

B. Synthesis of3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-O-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3-bromophenol, and4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dioneto replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (67%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.59(s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.71-6.65 (m, 1H), 6.61 (d, J=8.4 Hz,1H), 6.54 (s, 1H), 6.33-6.25 (m, 2H), 4.89-4.71 (m, 2H), 4.25-4.02 (m,4H), 3.99 (s, 1H), 3.83 (s, 6H).

C. Synthesis of3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onewas obtained (83%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ6.86(d, J=8.5 Hz, 1H), 6.71-6.67 (m, 1H), 6.66-6.60 (m, 2H), 6.32-6.25 (m,2H), 5.11 (s, 1H), 4.94-4.76 (m, 2H), 4.23-4.07 (m, 5H), 3.84 (s, 3H),3.74 (s, 3H).

Preparation 97 Synthesis of3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one

To a solution of 4,7-dimethoxy-1H-indole-2,3-dione (1.8 g, 8.7 mmol) inanhydroud N,N-dimethylformamide (20 mL) and anhydrous tetrahydrofuran(120 mL) at ambient temperature was added cesium carbonate (11.4 g, 35.0mmol), The mixture was stirred at ambient temperature for 30 min and1-bromo-2-(2-methoxyethoxy)ethane (2.35 mL, 17.4 mmol) was added in oneportion. The mixture was stirred at ambient temperature for 16 h,concentrated in vacuo to a small volume and poured into ice water (300mL). The mixture was extracted with ethyl acetate and the combinedorganic extracts were filtered through a pad of diatomaceous earth. Thefiltrate was dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. Trituration of the residue in hexanes afforded4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione (2.2 g,82%).

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3-bromophenol, and4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1H-indole-2,3-dione toreplace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-onewas obtained (53%): MS (ES+) m/z 443.9 (M−17).

B. Synthesis of3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-onewas obtained (89%) as a yellow solid: MS (ES+) m/z 446.0 (M+1).

Preparation 98 Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneA. Synthesis of6-[2-(2-methoxyethoxy)ethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione

Following the procedure as described in PREPARATION 97A and makingnon-critical variations using2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey andSternbach, Synthesis 1993:993-997) to replace4,7-dimethoxy-1H-indole-2,3-dione,6-[2-(2-methoxyethoxy)ethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dionewas obtained (82%): ¹H NMR (300 MHz, DMSO-d₆) δ7.05 (s, 1H), 6.78 (s,1H), 4.37-4.32 (m, 2H), 4.24-4.17 (m, 2H), 3.74 (t, J=5.5 Hz, 2H), 3.56(t, J=5.5 Hz, 2H), 3.50-3.44 (m, 2H), 3.36-3.30 (m, 2H), 3.14 (s, 3H).

B. Synthesis of8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3-bromophenol, and6-[2-(2-methoxyethoxy)ethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dioneto replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained (19%): MS (ES+) m/z 441.9 (M−17).

C. Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-onewas obtained (54%) as a pale yellow solid: MS (ES+) m/z 443.9 (M+1).

Preparation 99 Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-oneA. Synthesis of6-(4-methoxybenzyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione

To a mixture of 1,3-benzo[d]thiazol-6-amine (10.0 g, 66.6 mmol) and4-anisaldehyde (8.5 mL, 70 mmol) in 1,2-dichloroethane (350 mL) atambient temperature was added sodium triacetoxyborohydride (28.2 g,133.0 mmol). The mixture was stirred at ambient temperature for 16 h and1 N aqueous sodium hydroxide was added. The organic layer wasconcentrated in vacuo to a small volume, causing a precipitate to bedeposited. The solid was collected by filtration to affordN-(4-methoxybenzyl)-1,3-benzo[d]thiazol-6-amine (16.5 g, 90%) as acolorless solid. A mixture of oxalyl chloride (6.1 g, 48 mmol) andN-(4-methoxybenzyl)-1,3-benzo[d]thiazol-6-amine (1.3 g, 4.8 mmol) in asealed tube was heated at 140° C. for 1 h. The mixture was allowed tocool to ambient temperature during which time a precipitate wasdeposited. The solid was filtered, washed with hexanes and dried toafford 6-(4-methoxybenzyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione (1.2g, 76%) as an orange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H),8.27 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 1H),6.86 (d, J=8.6 Hz, 2H), 4.87 (s, 2H), 3.68 (s, 3H).

B. Synthesis of8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol toreplace 3-bromophenol, and6-(4-methoxybenzyl)-6H-[1,3]thiazolo[5,4-e]indole-7,8-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-onewas obtained (39%) as a colorless solid: MS (ES+) m/z 477.1 (M+1).

C. Synthesis of8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using8-hydroxy-8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-onewas obtained (89%) as a colorless solid: MS (ES+) m/z 461.1 (M+1).

Preparation 100 Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 3-(benzyloxy)phenol to replace3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (75%): MS (ES+) m/z 496.0 (M−17).

B. Synthesis of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-onewas obtained (57%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.01(s, 1H), 7.45-7.16 (m, 15H), 7.13-7.01 (m, 2H), 6.96 (s, 1H), 6.85-6.76(m, 1H), 6.71-6.65 (m, 1H), 6.55-6.49 (m, 1H), 6.49-6.42 (m, 1H), 5.10(s, 1H), 4.99 (s, 2H).

Preparation 101 Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 4-(benzyloxy)phenol to replace3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-onewas obtained (76%): ¹H NMR (300 MHz, CDCl₃) δ 8.63 (s, 1H), 7.46-7.40(m, 1H), 7.38-7.21 (m, 15H), 7.13-7.06 (m, 2H), 6.97 (d, J=8.8 Hz, 1H),6.92 (s, 1H), 6.86 (dd, J=8.8, 3.0 Hz, 1H), 6.52-6.45 (m, 2H), 4.85 (s,2H), 4.53 (s, 1H).

B. Synthesis of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-onewas obtained (67%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.51(br s, 1H), 7.41-7.16 (m, 16H), 7.10-7.03 (m, 2H), 7.02-6.97 (m, 1H),6.96 (s, 1H), 6.85-6.79 (m, 1H), 6.58-6.48 (m, 2H), 5.17 (s, 1H), 4.92(s, 2H).

Preparation 102 Synthesis of 1-(bromomethyl)-2-(difluoromethyl)benzeneA. Synthesis of 1-(difluoromethyl)-2-methylbenzene

To a solution of o-tolualdehyde (5.00 g, 41.6 mmol) in anhydrousdichloromethane (50 mL) was added a solution of (diethylamino)sulfurtrifluoride (6.70 g, 41.6 mmol) in anhydrous dichloromethane (30 mL) atambient temperature. The mixture was stirred for 16 h at ambienttemperature and saturated aqueous sodium bicarbonate (200 mL) was added.The mixture was extracted with dichloromethane (2×150 mL) and diethylether (100 mL). The combined organic phases were dried over sodiumsulfate, filtered, and concentrated in vacuo. The resultant liquid waspurified by column chromatography and eluted with dichloromethane toafford 1-(difluoromethyl)-2-methylbenzene (2.90 g, 49%) as a yellowliquid: ¹H NMR (300 MHz, CDCl₃) δ7.48 (d, J=7.6 Hz, 1H), 7.35 (dd,J=7.0, 7.0 Hz, 2H), 7.24 (dd, J=14.9, 7.6 Hz, 1H), 6.78-6.70 (m, 1H),2.42 (s, 3H).

B. Synthesis of 1-(bromomethyl)-2-(difluoromethyl)benzene

To a solution of 1-(difluoromethyl)-2-methylbenzene (2.90 g, 20.4 mmol)in carbon tetrachloride (50 mL) was added N-bromosuccinimide (3.63 g,20.4 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol).The mixture was heated at reflux for 16 h. Further2,2′-azobis(2-methylpropionitrile) (0.167 g, 1.02 mmol) was added, themixture was heated at reflux for 4 h, allowed to cool to ambienttemperature, diluted with dichloromethane (175 mL) and washed with water(2×175 mL) and saturated sodium bicarbonate (150 mL). The organic phasewas dried over sodium sulfate, filtered, and concentrated in vacuo. Theresultant residue was purified by column chromatography and eluted witha 0% to 10% gradient of ethyl acetate in dichloromethane to afford1-(bromomethyl)-2-(difluoromethyl)benzene as a yellow solid: ¹H NMR (300MHz, CDCl₃) δ7.58-7.56 (m, 1H), 7.43-7.37 (m, 3H), 6.95 (t, 55.2 Hz,1H), 4.59 (s, 2H).

Preparation 103 Synthesis of [3-(difluoromethyl)pyridin-2-yl]methanolhydrochloride A. Synthesis of 3-(difluoromethyl)-2-methylpyridine

To a solution of 2-methylpyridine-3-carbaldehyde (3.8 g, 31.4 mmol) indichloromethane (60 mL) was added (diethylamino)sulfur trifluoride (4.14mL, 31.4 mmol). After 16 h at ambient temperature, the reaction wasquenched by the addition of saturated aqueous sodium bicarbonate (200mL) and extracted with dichloromethane (200 mL). The organic phase waswashed with brine (200 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 0% to 30% gradient of diethyl ether in dichloromethaneto afford 3-(difluoromethyl)-2-methylpyridine (2.56 g, 57%) as a yellowliquid: ¹H NMR (300 MHz, CDCl₃) δ8.58 (d, J=4.8 Hz, 1H), 7.80 (d, J=7.8Hz, 1H), 7.21 (dd, J=7.8, 5.2 Hz, 1H), 6.82-6.72 (m, 1H), 2.63 (s, 3H).

B. Synthesis of 3-(difluoromethyl)-2-methylpyridine-1-oxide

To a solution of 3-(difluoromethyl)-2-methylpyridine (2.56 g, 17.9 mmol)in dichloromethane was added 3-chloroperbenzoic acid (6.01 g, 26.8 mmol)at ambient temperature. After stirring for 2 h, the mixture was dilutedwith a 1 M aqueous sodium hydroxide (50 mL) and extracted withdichloromethane (4×50 mL). The organic phase was washed with brine (150mL), dried over sodium sulfate, filtered and concentrated in vacuo toafford 3-(difluoromethyl)-2-methylpyridine-1-oxide as a yellow oil (2.22g, 78%): ¹H NMR (300 MHz, CDCl₃) δ8.36 (d, J=6.5 Hz, 1H), 7.40 (d, J=7.9Hz, 1H), 7.23 (m, 1H), 6.80-6.70 (m, 1H), 2.57 (s, 3H).

C. Synthesis of [3-(difluoromethyl)pyridin-2-yl]methanol hydrochloride

3-(Difluoromethyl)-2-methylpyridine-1-oxide (2.22 g, 14.0 mmol) andacetic anhydride (10 mL, 100 mmol) were heated at 80° C. for 1 h. Thereaction mixture was allowed to cool to ambient temperature, diethylether (100 mL) was added and the mixture was washed with a 1 M aqueoussodium hydroxide (100 mL), water (50 mL), and brine (50 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated in vacuo.The residue was taken up in methanol (70 mL) and potassium carbonate(20.2 g, 14.6 mmol) was added. The mixture was stirred at ambienttemperature for 1 h, concentrated in vacuo and the residue was taken upin water and extracted with ethyl acetate (3×50 mL). The organic phasewas washed with brine (100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was taken up in anhydrous diethylether and the product was precipitated by the addition of a 4 M solutionof hydrogen chloride in 1,4-dioxane to afford[3-(difluoromethyl)pyridin-2-yl]methanol hydrochloride (0.700 g, 26%) asa colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.89 (s, 2H), 8.81 (d,J=5.2 Hz, 1H), 8.44 (d, J=7.6 Hz, 1H), 7.83 (m, 1H), 7.48-7.38 (m, 1H),4.89 (s, 2H).

Preparation 104 Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

To a solution of 2,3-dihydro-1,4-benzodioxin-5-ol (3.60 g, 23.7 mmol) inanhydrous tetrahydrofuran (80 mL) at 0° C. was added isopropylmagnesiumchloride (11.8 mL, 2 M solution in tetrahydrofuran, 23.7 mmol). Themixture was stirred at 0° C. for 45 min, concentrated in vacuo, and1,2-dichloroethane (60 mL) was added. The mixture was cooled to 0° C.and a solution of 1-benzhydrylindoline-2,3-dione (4.94 g, 15.8 mmol) in1,2-dichloroethane (70 mL) was added. The reaction mixture was allowedto warm to ambient temperature and stirred for 60 h, and heated to 83°C. and stirred for 3.5 h. The reaction mixture was allowed to cool toambient temperature, concentrated in vacuo and saturated aqueousammonium chloride (250 mL) was added. The mixture was extracted withethyl acetate (250 mL followed by 2×100 mL). The organic phase waswashed with water (150 mL) and brine (150 mL), dried over sodium sulfateand filtered. The filtrate was concentrated in vacuo. The residue wastaken up in ethyl acetate and a solid was precipitated by the additionof hexanes to afford1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(5.10 g, 69%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.14 (s,1H), 7.43-7.30 (m, 9H), 7.22 (d, J=8.7 Hz, 1H), 6.97-6.79 (m, 3H), 6.52(s, 1H), 6.44 (d, J=8.7 Hz, 1H) 6.26 (d, J=7.8 Hz, 1H), 4.22 (s, 4H).

B. Synthesis of1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-onewas obtained (82%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.11 (s, 1H), 7.39-7.24 (m, 9H), 6.95-6.79 (m, 3H), 6.58 (d, J=8.0 Hz,1H), 6.35-6.30 (m, 2H), 4.21 (s, 4H).

Preparation 105 Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-oneA. Synthesis of 1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dione

Following the procedure as described in PREPARATION 26A and makingnon-critical variations using 4,6-dimethoxy-1H-indole-2,3-dione toreplace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, andbromodiphenylmethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dione was obtained (90%):¹H NMR (300 MHz, DMSO-d₆) δ7.49-7.19 (m, 10H), 6.72 (s, 1H), 6.21 (d,J=1.5 Hz, 1H), 5.87 (d, J=1.5 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H).

B. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 2A and makingnon-critical variations using 4-(benzyloxy)phenol to replace3-bromophenol, and 1-(diphenylmethyl)-4,6-dimethoxy-1H-indole-2,3-dioneto replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione,1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-onewas obtained (50%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.81(s, 1H), 7.34-7.16 (m, 10H), 6.82 (s, 1H), 6.55 (s, 1H), 6.31 (s, 1H),6.14 (d, J=1.8 Hz, 1H), 5.64 (d, J=1.8 Hz, 1H), 4.22-4.10 (m, 4H), 3.92(s, 1H), 3.77 (s, 3H), 3.49 (s, 3H).

C. Synthesis of1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-one

Following the procedure as described in PREPARATION 4C, and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-oneto replace4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-onewas obtained (92%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.35-7.25 (m, 8H), 7.21-7.14 (m, 2H), 6.87 (s, 1H), 6.61 (s, 1H), 6.27(s, 1H), 6.17 (d, J=1.8 Hz, 1H), 5.68 (d, J=1.8 Hz, 1H), 5.02 (s, 1H),4.24-4.10 (m, 4H), 3.73 (s, 3H), 3.48 (s, 3H), 3.47 (s, 1H).

Preparation 106 Synthesis of1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-oneA. Synthesis of1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one

To a stirred solution of quinoxalin-6-ol (King et al.; J. of the Chem.Society 1949:3012.) (11.2 g, 76.66 mmol) in tetrahydrofuran (800 mL) wasadded isopropylmagnesium chloride (38.3 mL, 2.0 M THF solution, 76.60mmol) at −40° C. to −30° C. The mixture was allowed to stir at 0° C. for2 h, followed by the addition of 1-(diphenylmethyl)-1H-indole-2,3-dione(20.00 g, 63.84 mmol) in tetrahydrofuran (400 mL). The mixture wasstirred at ambient temperature for 20 h, and quenched with saturatedammonium chloride solution and extracted with ethyl acetate (3×1000 mL).The organic layer was washed with water and brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo, andthe residue was purified by column chromatography(dichloromethane/methanol, 100/1) to give1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one(10.0 g, 34%): ¹H NMR (300 MHz, CDCl₃) δ 10.21 (s, 1H), 8.47 (s, 1H),7.97-7.92 (m, 2H), 7.60-7.58 (m, 2H), 7.54-7.49 (m, 4H), 7.46-7.35 (m,6H), 7.14 (s, 1H), 7.05-7.00 (m, 1H), 6.89-6.87 (m, 1H), 6.56-6.52 (m,1H).

B. Synthesis of1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one

To thionyl chloride (60 mL) was added1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one(3.0 g, 6.53 mmol) at −10° C. The resulting reaction mixture was stirredat 0° C. for 1 h, and concentrated in vacuo. The residue was dissolvedin acetic acid (150 mL), followed by the addition of zinc dust (4.50 g,68.81 mmol). The resulting mixture was stirred at ambient temperaturefor 40 min. The solids were filtered out. The filtrate was concentratedin vacuo. The residue was dissolved in ethyl acetate (200 mL), washedwith water and brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated in vacuo, the residue was purified bycolumn chromatography (dichloromethane/methanol 200/1) to give1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one(2.40 g, 83%): MS (ES+) m/z 444 (M+1).

EXAMPLE 1 Synthesis of2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

To a cooled (−78° C.) solution of1,3-bis(hydroxymethyl)-3-(5-hydroxy-2-methyl-1,3-benzothiazol-6-yl)-1,3-dihydro-2H-indol-2-one(1.70 g, 4.7 mmol) in anhydrous tetrahydrofuran (30 mL) was addedtri-n-butylphosphine (0.80 mL, 5.7 mmol), followed by diethylazodicarboxylate (1.05 mL, 6.7 mmol). The reaction mixture was allowedto warm to ambient temperature and was stirred for 2 h. The reactionmixture was cooled to 0° C. and a 28% aqueous solution of ammonia (10mL) was added. The reaction mixture was stirred for 1 h at 0° C. and wasacidified to pH 6 by the dropwise addition of 10% aqueous hydrochloricacid. The reaction mixture was extracted with ethyl acetate (3×50 mL)and the combined organic solution was washed with brine (2×50 mL), driedover sodium sulfate, filtered and concentrated. The resultant solid wastriturated with diethyl ether (50 mL), collected by vacuum filtration,washed with diethyl ether (20 mL) and dried under high vacuum to afford2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one(1.03 g, 70%): mp>250° C. (ethyl acetate); ¹H NMR (300 MHz, DMSO-d₆)δ10.75 (br s, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.26-7.19 (m, 1H), 7.10 (d,J=8.6 Hz, 1H), 7.02-6.86 (m, 3H), 4.86-4.74 (m, 2H), 2.60 (s, 3H); ¹³CNMR (75 MHz, DMSO-d₆) δ177.7, 160.1, 148.9, 141.7, 138.5, 132.7, 128.6,128.0, 123.4, 122.7, 122.1, 119.9, 109.7, 108.3, 80.9, 57.8, 20.0; MS(ES+) m/z 309.1 (M+1).

EXAMPLE 1.1 Synthesis of1-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.23 g, 0.79 mmol), 6-methyl-2-pyridinemethanol (0.13 g, 1.07 mmol) andtriphenylphosphine (0.30 g, 1.14 mmol) in benzene (10 mL) under nitrogenwas slowly added a solution of diethyl azodicarboxylate (0.22 g, 1.27mmol) in tetrahydrofuran (6 mL). The resulting mixture was stirred atambient temperature for 16.5 h. The solvents were removed under reducedpressure, and the residue was taken up into 2 M sodium carbonate (50 mL)and extracted with dichloromethane (3×30 mL). The combined organicsolution was washed with brine (50 mL), dried with sodium sulfate,filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography with hexanes/ethyl acetate (2:1) gave1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.13 g, 41%) as a colorless solid: mp 183-185° C. (hexanes/diethylether); ¹H NMR (300 MHz, CDCl₃) δ7.56 (dd, J=7.8, 7.5 Hz, 1H), 7.23-7.16(m, 2H), 7.10-7.00 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.32(s, 1H), 5.23 (d, J=15.9 Hz, 1H), 4.958 (d, J=9.0 Hz, 1H), 4.956 (d,J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11 (m,2H), 2.59 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 158.2, 155.4, 154.7,144.8, 142.2, 138.4, 138.2, 132.3, 129.0, 124.0, 123.7, 122.9, 121.2,118.8, 111.8, 109.8, 99.6, 80.3, 64.7, 64.1, 58.3, 45.7, 24.1; MS (ES+)m/z 401.0 (M+1).

EXAMPLE 1.2 Synthesis of1-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.30 g, 1.00 mmol), 3-pyridinemethanol (0.15 mL, 1.50 mmol) andtriphenylphosphine (0.36 g, 1.36 mmol) in tetrahydrofuran (7 mL) undernitrogen was slowly added a solution of diethyl azodicarboxylate (0.29g, 1.67 mmol) in tetrahydrofuran (3 mL). The resulting mixture wasstirred at ambient temperature for 21 h. The solvents were removed underreduced pressure, and the residue was taken up into 2 M sodium carbonate(50 mL) and extracted with dichloromethane (2×30 mL). The combinedorganic solution was dried with sodium sulfate, filtered andconcentrated under reduced pressure. The filterate was purified by flashcolumn chromatography with dichloromethane/isopropanol (49:1, increasedto 29:1) to give a mixture of the desired product and triphenylphosphineoxide. This material was acidified with 1 M hydrochloric acid (30 mL)and extracted with diethyl ether (3×30 mL). The aqueous solution wasmade basic with 5 M sodium hydroxide and extracted with dichloromethane(3×30 mL). Once dried with sodium sulfate, the organic solution wasconcentrated under reduced pressure to afford1-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.22 g, 57%) as a colorless solid: mp 142-143° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.93-8.47 (m, 2H), 7.79 (d,J=7.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.23 (ddd, J=7.8, 7.8, 0.9 Hz, 1H),7.18 (d, J=7.2 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.81 (d, J=7.8 Hz,1H), 6.50 (s, 1H), 6.19 (s, 1H), 5.09 (d, J=15.8 Hz, 1H), 4.924 (d,J=9.0 Hz, 1H), 4.919 (d, J=15.8 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H),4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.8,155.4, 148.0, 147.5, 144.9, 141.5, 138.5, 137.0, 132.2, 129.1, 124.3,124.0, 120.8, 111.5, 109.0, 99.6, 80.2, 64.6, 64.0, 58.1, 41.7; MS (ES+)m/z 386.7 (M+1).

EXAMPLE 1.3 Synthesis of1′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a stirred solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.84 g, 3.0mmol) and (1-isopropyl-2,5-dimethyl-1H-pyrrol-3-yl)methanol (0.50 g, 3.0mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwisetributylphosphine (0.90 g, 1.5 mmol). The solution was cooled to 0° C.and diethyl azodicarboxylate (0.78 g, 4.5 mmol) was added. The solutionwas stirred at ambient temperature for 16 h then quenched with saturatedammonium chloride (50 mL). The aqueous solution was extracted with ethylacetate (200 mL), dried on magnesium sulfate, filtered and concentratedin vacuo to dryness. The residue was purified by flash chromatographywith ethyl acetate in hexanes (15% to 50% gradient) to afford1′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.32 g, 24%) as a colorless solid: mp 169-171° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.27-7.20 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.02-6.95 (m, 2H),6.49 (s, 1H), 6.09 (s, 1H), 5.85-5.82 (m, 2H), 5.77 (br s, 1H), 4.77(ABq, 2H), 4.69 (ABq, 2H), 4.37 (sep, J=7.0 Hz, 1H), 2.33 (s, 3H), 2.22(s, 3H), 1.43 (d, J=7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ194.7, 177.2,155.9, 148.7, 142.9, 142.2, 132.5, 128.7, 127.0, 125.5, 123.6, 122.9,119.9, 113.0, 109.6, 107.6, 103.2, 101.4, 93.5, 80.5, 58.2, 47.3, 37.0,22.2, 14.1, 11.5; MS (ES+) m/z 431.20 (M+1).

EXAMPLE 1.4 Synthesis of5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of3-[5-(benzyloxy)-2-hydroxyphenyl]-1-[(5-chloro-2-thienyl)methyl]-3-hydroxymethyl-1,3-dihydro-2H-indol-2-one(2.71 g, 5.52 mmol) in anhydrous tetrahydrofuran (60 mL) was addeddropwise tributylphosphine (1.39 g, 6.90 mmol). The solution was cooledto 0° C. and di-tert-butyl azodicarboxylate (1.59 g, 6.90 mmol) wasadded. The solution was stirred at 0° C. for 20 min then quenched withaqueous 10% hydrochloric acid (50 mL). The aqueous solution wasextracted with ethyl acetate (3×100 mL), brine (3×50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to dryness.The residue was purified by flash column chromatography with ethylacetate in hexanes (20%) to give5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.36 g, 90%) as a colorless solid: mp 132-135° C.; ¹H NMR (300 MHz,DMSO-d₆) 7.33-7.21 (m, 7H), 7.16-7.12 (m, 2H), 7.02 (ddd, J=7.4, 7.4,1.0 Hz, 1H), 6.97 (d, J=3.8 Hz, 1H), 6.90-6.32 (m, 2H), 6.21 (d, J=2.3Hz, 1H), 5.05 (ABq, 2H), 4.82 (s, 2H), 4.72 (ABq, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ176.6, 155.0, 153.6, 141.9, 138.6, 137.4, 132.0 130.3, 129.4,128.8, 128.2, 128.1, 127.9, 127.1, 124.3, 123.8, 116.6, 110.8, 110.0,109.9, 79.4, 70.4, 58.1, 38.9; MS (ES+) m/z 476.3 (M+1), 474.3 (M+1).

EXAMPLE 1.5 Synthesis of7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a suspended mixture of7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(4.70 g, 12.4 mmol) in anhydrous tetrahydrofuran (120 mL) was addedtributylphosphine (3.8 mL, 15.5 mmol), followed by additional ofdi-tert-butyl azodicarboxylate (3.58 g, 15.5 mmol) in anhydroustetrahydrofuran (25 mL) at 0° C. The reaction mixture was stirred at 0°C. for 1 h and at ambient temperature for 16 h. The reaction wasquenched by addition of saturated aqueous ammonium chloride solution(150 mL) and extracted with ethyl acetate (3×200 mL). The combinedorganic solution was washed with brine (100 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo to dryness. Theresidue was purified by column chromatography with ethyl acetate inhexanes (10% to 30% gradient) to give7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.4g, 53%) as a colorless solid: mp 240° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ10.88 (s, 1H), 7.34 (dd, J=8.1, 1.0 Hz, 1H), 7.10 (d, J=7.2Hz, 1H), 6.93 (dd, J=8.1, 7.5 Hz, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.93(dd, J=2.9, 0.8 Hz, 2H), 4.77 (d, J=9.4 Hz, 1H), 4.65 (d, J=9.4 Hz, 1H);¹³C NMR (75 MHz, DMSO-d₆) δ 178.1, 155.3, 148.2, 141.6, 141.1, 134.2,131.4, 123.8, 122.8, 119.4, 103.1, 102.0, 101.3, 93.1, 79.9, 58.8; MS(ES+) m/z 360.2 (M+1), 362.2 (M+1); MS (ES−) m/z 358.2 (M−1), 360.2(M−1).

EXAMPLE 1.6 Synthesis of1′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To an ice-cold stirring suspension of (3-isopropylisoxazol-5-yl)methanol(0.338 g, 2.4 mmol) in N,N-dimethylformamide (20 mL) was added asolution of N-(chloromethylene)-N-methylmethanaminium chloride (0.36 g,2.8 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred atambient temperature for 30 min and then transferred to a suspendedmixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.56 g, 2.0 mmol), cesium carbonate (1.95 g, 6.0 mmol) inN,N-dimethylformamide (4 mL). The reaction mixture was stirred atambient temperature for 16 h and filtered. The solid was washed withacetone (100 mL). The filtrate was concentrated in vacuo. The residuewas purified by column chromatography with ethyl acetate in hexanes (10%to 30% gradient) to give1′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.50 g, 60%) as a colorless solid: mp 132-136° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) 87.34 (ddd, J=7.7, 7.7, 1.2Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.08 (ddd,J=7.5, 7.5, 0.8 Hz, 1H), 6.71 (s, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 5.93(d, J=1.0 Hz, 2H), 5.08 (s, 2H), 4.82 (d, J=9.4 Hz, 1H), 4.72 (d, J=9.4Hz, 1H), 3.03 (m, 1H), 1.19 (d, J=6.9 Hz, 6H); ¹³C NMR (75 MHz, DMSO-d₆)δ176.4, 168.9, 166.3, 155.2, 148.3, 141.6, 141.5, 131.4, 128.8, 123.6,123.2, 119.5, 109.1, 102.8, 101.3, 101.1, 93.2, 79.5, 57.2, 35.6, 25.8,21.2; MS (ES+) m/z 405.3 (M+1).

EXAMPLE 1.7 Synthesis of1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.6 and makingnon-critical variations using (4-bromothiophen-2-yl)methanol to replace(3-isopropylisoxazol-5-yl)methanol,1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.59 (d, J=1.5 Hz, 1H), 7.35-7.18 (m, 4H), 7.06 (ddd, J=7.4, 7.4, 0.7Hz, 1H), 6.71 (s, 1H), 6.12 (s, 1H), 5.93 (d, J=2.2 Hz, 2H), 5.11 (d,J=6.9 Hz, 2H), 4.81 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H); ¹³C NMR(75 MHz, DMSO-d₆) δ176.5, 155.4, 148.4, 141.7, 141.4, 140.9, 131.6,129.2, 128.9, 123.8, 123.7, 123.3, 119.6, 109.4, 108.0, 102.7, 101.5,93.4, 79.7, 57.4, 38.1; MS (ES+) m/z 478.1 (M+23), 480.1 (M+23).

EXAMPLE 1.8 Synthesis of1′-(1-benzofuran-2-ylmethyl)spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.6 and makingnon-critical variations using benzofuran-2-ylmethanol to replace(3-isopropylisoxazol-5-yl)methanol,1-(1-benzofuran-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp 167-168° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ7.60 (dd, J=7.0, 1.5 Hz, 1H), 7.50 (d, J=8.2Hz, 1H,), 7.33-7.19 (m, 5H), 7.05 (ddd, J=7.4, 7.4, 0.9 Hz, 1H), 6.98(s, 1H), 6.72 (s, 1H), 6.22 (s, 1H), 5.94 (d, J=4.3 Hz, 2H), 5.15 (d,J=6.0 Hz, 2H), 4.84 (d, J=9.4 Hz, 1H), 4.73 (d, J=9.4 Hz, 1H); ¹³C NMR(75 MHz, DMSO-d₆) δ176.5, 155.3, 154.3, 152.2, 148.4, 141.8, 141.7,131.6, 128.8, 127.8, 124.4, 123.6, 123.2, 123.0, 121.1, 119.7, 110.9,109.5, 105.2, 102.9, 101.5, 93.3, 79.7, 57.5, 37.2; MS (ES+) m/z 412.3(M+1).

EXAMPLE 1.9 Synthesis of1-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a mixture ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.281 g, 1.0mmol) and (2-methyl-5-(trifluoromethyl)oxazol-4-yl)methanol (0.18 g, 1.0mmol) in anhydrous tetrahydrofuran (8 mL) was added tributylphosphine(0.30 g, 1.5 mmol) at 0° C., followed by additional ofN,N,N′/N′-tetramethylazodicarboxamide (0.26 g, 1.5 mmol). The reactionmixture was stirred at 0° C. for 1 h and stirred at ambient temperaturefor 16 h. The reaction mixture was quenched with aqueous ammoniumchloride (25%, 50 mL) and extracted with ethyl acetate (3×40 mL). Thecombined organic solution was washed with brine (30 mL), dried overanhydrous sodium sulfate and concentrated in vacuo to dryness. Theresidue was purified by column chromatography with ethyl acetate inhexanes (10% to 30% gradient) to give1′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.30 g, 68%) as a colorless solid: mp 136-137° C. (diethylether/hexane); ¹H NMR (300 MHz, DMSO-d₆) δ 7.32 (ddd, J=7.7, 1.2, 1.2Hz, 1H), 7.19 (dd, J=7.6, 1.0 Hz, 1H), 7.07-7.03 (m, 2H), 6.70 (s, 1H),6.29 (s, 1H), 5.93 (dd, J=5.0, 0.7 Hz, 2H), 4.98 (q, J=16.4 Hz, 2H),4.75 (dd, J=20.8, 9.4 Hz, 2H), 2.46 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.5, 163.6, 155.1, 148.2, 141.9, 141.5, 137.6 (d, ³J_(CF)=2.1 Hz),133.5 (q, ²J_(CF)=42.7 Hz), 131.6, 128.7, 123.5, 123.0, 119.8, 119.2 (q,¹J_(CF)=266.9 Hz), 109.0, 103.0, 101.3, 93.1, 79.3, 57.2, 34.9, 13.4; MS(ES+) m/z 445.3 (M+1).

EXAMPLE 1.10 Synthesis of(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneand(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

5,6-Dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.04 g) was dissolved with heating and sonication in dimethylsulfoxide(0.3 mL). Acetonitrile (0.3 mL) and methyl tent-butyl ether (2.0 mL)were added and the mixture was submicron filtered. The mixture wasinjected onto a Waters LC/MS autopurification system (Waters Inc.,Milford, Mass.) equipped with a CHIRALPAK-IA (Chiral Technologies, Inc.,West Chester, Pa.) HPLC column (21 mm i.d.×250 mm length, 20 μm particlediameter) and was eluted over a run time of 20 min with methyltert-butyl ether/acetonitrile (9/1) at a flow rate of 15 mL/min with UVdetection at 254 nm. 35 replicate injections were performed under theseconditions, corresponding to a total of 1.40 g of the racemate.Following resolution, the appropriate fractions were concentrated todryness in vacuo and the resultant solid was triturated with methanol(15 mL), collected by vacuum filtration and dried under high vacuum.

The first enantiomer to elute was(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,which was obtained as a colorless solid with a 67% recovery (0.472 g):mp 255-256° C. (methanol); ¹H NMR (300 MHz, DMSO-d₆) δ10.56 (br s, 1H),7.26-7.18 (m, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.98-6.89 (m, 2H), 6.49 (s,1H), 6.38 (s, 1H), 4.77 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H),4.52-4.43 (m, 2H), 2.99-2.91 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.7,131.0, 160.6, 141.8, 133.0, 128.6, 123.8, 122.3, 120.8, 119.7, 119.0,109.7, 92.4, 79.9, 72.1, 57.3, 28.4; MS (ES+) m/z 278.0 (M+1).

The second enantiomer to elute was(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,which was obtained as a colorless solid with a 60% recovery (0.423 g):mp 256-257° C. (methanol); ¹H NMR (300 MHz, DMSO-d₆) δ10.56 (br s, 1H),7.26-7.18 (m, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.98-6.89 (m, 2H), 6.49 (s,1H), 6.38 (s, 1H), 4.77 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H),4.52-4.43 (m, 2H), 2.99-2.91 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.7,131.0, 160.6, 141.8, 133.0, 128.6, 123.8, 122.3, 120.8, 119.7, 119.0,109.7, 92.4, 79.9, 72.1, 57.3, 28.4; MS (ES+) m/z 278.0 (M+1).

EXAMPLE 1.11 Preparation of(R)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-oneand(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.14 g) was dissolved in hot dimethylsulfoxide (0.4 mL). Acetonitrile(0.4 mL) and methyl tert-butyl ether (2.2 mL) were added and the mixturewas submicron filtered. The mixture was injected onto a Waters LC/MSautopurification system (Waters Inc., Milford, Mass.) equipped with aCHIRALPAK-IA (Chiral Technologies, Inc., West Chester, Pa.) HPLC column(30 mm i.d.×250 mm length, 20 μm particle diameter) and was eluted overa run time of 60 min with methyl tert-butyl ether/acetonitrile (98/2) ata flow rate of 30 mL/min with UV detection at 254 nm. Followingresolution, the appropriate fractions were concentrated to dryness invacuo and the resultant solid was triturated with water (30 mL),collected by vacuum filtration and dried under high vacuum.

The first enantiomer to elute was(R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,which was obtained as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆)δ10.57 (s, 1H), 7.24 (ddd, J=7.7, 7.7, 1.0 Hz, 1H), 7.09 (d, J=6.9 Hz,1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H),6.16 (s, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.60 (d, J=9.0 Hz, 1H), 4.20-4.15(m, 2H), 4.12-4.07 (m, 2H); MS (ES+) m/z 296.0 (M+1); [α]_(D) −36.61 (c1.0, DMSO).

The second enantiomer to elute was(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,which was obtained as a colorless solid; ¹H NMR (300 MHz, DMSO-d₆)δ10.57 (s, 1H), 7.24 (ddd, J=7.7, 7.7, 1.0 Hz, 1H), 7.09 (d, J=6.9 Hz,1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H),6.16 (s, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.60 (d, J=9.0 Hz, 1H), 4.20-4.15(m, 2H), 4.12-4.07 (m, 2H); MS (ES+) m/z 296.0 (M+1); [α]_(D) +36.65 (c1.0, DMSO).

EXAMPLE 1.12 Synthesis of(8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a mixture of (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride(5.0 g, 23.14 mmol) and thionyl chloride (5.0 g, 42.0 mmol) indichloromethane (50 mL) at 0° C. were added two drops ofN,N-dimethylformamide. The reaction mixture was allowed to warm toambient temperature and stirred for 16 h. The solvent was removed underreduced pressure, and the residue was dissolved in N,N-dimethylformamide(50 mL). To the above solution were added(8S)-2,3-dihydrospyro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(4.72 g, 15.98 mmol), cesium carbonate (16.3 g, 50.03 mmol) andpotassium iodide (1.0 g, 6.0 mmol). The reaction mixture was warmed upto 90° C. and stirred under nitrogen for 2.5 h. The reaction mixture wascooled to ambient temperature, concentrated to dryness under reducedpressure, and the residue was treated with water (50 mL) and sonicatedfor 0.5 h. The suspension was filtered, and washed with water (50 mL),dried under reduced pressure. The solid crude product was subjected tocolumn chromatography with dichloromethane/ethyl acetate (1:100-1:4) toafford(8S)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospyro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(5.45 g, 75%) as a colorless solid: mp 164-165° C. (methanol); ¹H NMR(300 MHz, DMSO-d₆) δ 8.62 (d, J=4.4 Hz, 1H), 8.20 (d, J=7.7 Hz, 1H),7.51 (dd, J=7.7, 5.0 Hz, 1H), 7.23-6.82 (m, 4H), 6.47 (s, 1H), 6.43 (s,1H), 5.21 (ABq, 2H), 4.73 (ABq, 2H), 4.18-4.04 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.5, 155.0, 152.9, 152.8, 144.5, 143.3, 138.2, 135.5,135.4, 132.4, 129.1, 126.1, 124.1, 123.9, 123.7, 123.4, 123.3, 122.8,122.5, 122.0, 112.2, 109.4, 99.0, 79.6, 64.6, 64.0, 57.7, 42.4, 42.3; MS(ES+) m/z 454.9.

EXAMPLE 1.13 Synthesis of(8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a mixture of(8S)-2,3-dihydrospyro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.3 g, 4.4 mmol), (5-(benzyloxy)pyridin-2-yl)methanol (1.23 g, 5.72mmol) and tributylphosphine (1.26 g, 6.23 mml) in tetrahydrofuran (150mL) at 0° C. was added diethyl azodicarboxylate (1.15 g, 6.62 mmol). Thereaction mixture was allowed to warm to ambient temperature and stirredfor 48 h. The reaction mixture was diluted with ethyl acetate (100 mL)and filtered, and the filtrate was concentrated under reduced pressure.The residue was dissolved in dichloromethane (150 mL), washed with 1 Mhydrochloric acid in water (3×30 mL), 1 M sodium hydroxide in water(3×30 mL), dried over magnesium sulfate, filtered, and the filtrate wasconcentrated to dryness. The residue was sonicated with methanol (30mL), and the solid product was filtered off to afford(8S)-1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-2,3-dihydrospyro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(1.54 g, 87%). To a mixture of(8S)-1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-2,3-dihydrospyro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.54 g, 3.12 mmol) and ammonium formate (1.0 g, 15.86 mmol) in methanol(50 mL) was added 10% palladium on carbon (0.5 g). The reaction mixturewas heated at reflux for 1 h under nitrogen. The reaction mixture wascooled to ambient temperature, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was subjected to columnchromatography with dichloromethanemethanol (20:1-10:1) to afford(8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospyro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.93 g, 50%) as a colorless solid: mp 256-258° C. (chloroform-hexane);¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.96 (d, J=2.7 Hz, 1H),7.23-6.85 (m, 6H), 6.45 (s, 1H), 6.34 (s, 1H), 4.97 (ABq, 2H), 4.79(ABq, 2H), 4.08-3.91 (m, 2H), 3.78-3.56 (m, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ178.4, 155.3, 152.9, 145.7, 144.6, 142.2, 138.3, 137.3, 132.1,128.8, 124.3, 124.0, 123.7, 122.5, 120.5, 111.7, 109.5, 99.4, 79.7,64.4, 63.4, 58.2, 44.9; MS (ES+) m/z 402.8 (M+1).

EXAMPLE 1.14 Synthesis of1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.2 and makingnon-critical variations using (5-bromopyrid-2-yl)methanol to replace3-pyridinemethanol,1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′-(1′H)-onewas obtained (32%) as a colorless solid: mp 201-202° C.; ¹H NMR (300MHz, CDCl₃) δ8.63 (d, J=2.4 Hz, 1H), 7.79 (dd, J=8.4, 2.1 Hz, 1H),7.24-7.16 (m, 3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H),6.51 (s, 1H), 6.28 (s, 1H), 5.15 (d, J=15.9 Hz, 1H), 4.94 (d, J=9.0 Hz,1H), 4.91 (d, J=15.9 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.22-4.11 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.5, 155.3, 154.1, 150.6, 144.7, 141.9,139.7, 138.3, 132.2, 128.9, 123.9, 123.6, 123.1, 121.0, 119.9, 111.6,109.4, 99.4, 80.1, 64.5, 63.9, 58.1, 45.5; MS (ES+) m/z 465.1 (M+1),467.1 (M+1).

EXAMPLE 1.15 Synthesis of1′-{[5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.6 and makingnon-critical variations using(5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl)methanol to replace(3-isopropylisoxazol-5-yl)methanol,1-{[5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (35%) as a colorless solid: mp 114-116° C.; ¹H NMR (300MHz, CDCl₃) δ7.55 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 7.28 (dd,J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5, 7.5 Hz,1H), 6.87 (d, J=7.8 Hz, 1H), 6.57 (s, 1H), 6.53 (s, 1H), 6.09 (s, 1H),5.87 (s, 2H), 4.96 (ABq, 2H), 4.82, (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 156.0, 155.2, 149.1, 142.4, 141.4, 137.7, 135.1, 131.9, 129.2,129.1, 127.8, 127.1, 125.9, 124.7, 124.2, 123.9, 121.6, 119.2, 113.9,108.6, 106.6, 102.8, 101.6, 93.8, 80.3, 58.2, 34.4; MS (ES+) m/z 540.3(M+1), 542.3 (M+1).

EXAMPLE 1.16 Synthesis of1′-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 1.6 and makingnon-critical variations using(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol(Nakatani et al., EP 2002/743670) to replace(3-isopropylisoxazol-5-yl)methanol,1′-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 180-182° C.; ¹H NMR (300MHz, CDCl₃) δ7.26-7.12 (m, 2H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d,J=7.8 Hz, 1H), 6.49 (s, 1H), 6.14 (s, 1H), 5.84 (d, J=5.3 Hz, 2H), 4.92(s, 2H), 4.75 (ABq, 2H), 3.86 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.3,156.2, 148.9, 142.4, 141.6, 139.6 (q, J=37.9 Hz), 132.0, 128.9, 128.7,124.1, 123.6, 122.7, 119.0, 110.6, 108.9, 103.4, 101.5, 93.6, 80.9,58.2, 37.2, 33.5; MS (ES+) m/z 478.3 (M+1), 480.3 (M+1).

EXAMPLE 1.17 Synthesis of1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A 10 mL pressure tube was charged withspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.28 g, 1.0mmol), 3-bromo-5-methoxypyridine (0.26 g, 1.4 mmol), palladium (II)acetate (0.038 g, 0.2 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.14 g, 0.24 mmol),cesium carbonate (0.46 g, 1.4 mmol) and 1,4-dioxane (1.2 mL). Thereaction mixture was heated at 100° C. for 25 min under microwaveirradiation and allowed to cool to ambient temperature. The mixture wasdiluted with dichloromethane (20 mL) and filtered through a pad ofdiatomaceous earth. The filtrate was concentrated in vacuo and theresidue purified by column chromatography eluted with a 0% to 15%gradient of ethyl acetate in hexanes to afford1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.097 g, 25%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ8.37 (d, J=6.2Hz, 2H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 2H), 7.18-7.09 (m, 1H), 6.95(d, J=7.9 Hz, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 5.88 (d, J=6.2 Hz, 2H),4.89 (ABq, 2H), 3.90 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.0, 156.3,156.0, 149.1, 142.5, 141.9, 138.9, 137.3, 131.9, 129.1, 129.0, 128.2,124.5, 119.2, 118.5, 109.6, 103.0, 101.6, 93.7, 80.7, 58.5, 56.0; MS(ES+) m/z 389.3 (M+1).

EXAMPLE 2 Synthesis of1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a mixture of1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one(10.6 g, 24.4 mmol) and cesium carbonate (23.8 g, 73.1 mmol) intetrahydrofuran (100 mL) was added chloroiodomethane (6.35 g, 36.6 mmol)under nitrogen. The mixture was stirred at ambient temperature for 3 h,then filtered through a pad of silica and rinsed with tetrahydrofuran(500 mL). The filtrate was concentrated in vacuo to dryness. The residuewas recrystallized from diethyl ether (20 mL) to afford1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(7.9 g, 72%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.41-7.27(m, 10H), 7.15 (dd, J=7.1, 1.5 Hz, 1H), 7.07 (s, 1H), 7.05-6.92 (m, 2H),6.55-6.49 (m, 2H), 6.34 (s, 1H), 4.86 (ABq, 2H), 3.80 (s, 3H), 2.01 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ178.1, 160.2, 159.2, 141.8, 137.8, 137.4,132.9, 128.70, 128.66, 128.48, 128.46, 128.2, 128.0, 127.9, 124.2,123.8, 123.1, 119.6, 112.2, 93.8, 80.4, 58.7, 57.7, 55.6, 16.1; MS (ES+)m/z 448.3 (M+1).

EXAMPLE 2.1 Synthesis of4′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using4-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,4′-chloro-1-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (49%) as a colorless solid: MS (ES+) m/z 479.9 (M+1), 481.9(M+1).

EXAMPLE 2.2 Synthesis of6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(10.1 g, 22.6 mmol) and cesium carbonate (22.1 g, 67.8 mmol) intetrahydrofuran (100.0 mL) was added chloroiodomethane (5.88 g, 33.9mmol). The mixture was stirred at ambient temperature for 3 h, thenfiltered through a pad of silica gel followed by tetrahydrofuran rinses(500.0 mL). The filtrate was concentrated in vacuo to dryness, andrecrystallized from diethyl ether (20.0 mL) in a Branson ultrasonicbench top water bath to afford6-bromo-1-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(7.3 g, 67%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.44-7.25(m, 10H), 7.15-7.09 (m, 2H), 7.07-6.90 (m, 4H), 6.56-6.49 (m, 2H), 5.03(d, J=9.1 Hz, 1H), 4.76 (d, J=9.1 Hz, 1H); MS (ES+) m/z 482.1 (M+1),484.0 (M+1).

EXAMPLE 2.3 Synthesis of1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4,5-dimethylphenyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless solid: mp 193-195° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.38-7.32 (m, 10H), 7.14-6.92(m, 4H), 6.75-6.78 (m, 1H), 6.55-6.50 (m, 1H), 6.37-6.31 (m, 1H),4.99-4.94 (m, 1H), 4.73-4.65 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ177.9, 159.0, 141.7, 138.4, 137.7, 137.4, 132.8,129.4, 128.6, 128.4, 128.1, 127.9, 127.8, 126.3, 123.8, 123.0, 112.2,111.4, 79.7, 58.7, 57.8, 20.3, 19.3; MS (ES+) m/z 432.3 (M+1).

EXAMPLE 2.4 Synthesis of1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 228-229° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.39-7.25 (m, 10H), 7.06 (s, 1H), 6.90-6.87 (m, 1H), 6.72-6.65 (m, 1H),6.42-6.38 (m, 3H), 4.83 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 3.02-2.97 (m,2H); MS (ES+) m/z 464.1 (M+1).

EXAMPLE 2.5 Synthesis of1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (87%) as a colorless solid: mp 194-196° C. (methanol); ¹HNMR (300 MHz, CDCl₃) δ7.42-7.25 (m, 10H), 7.10-7.04 (m, 2H), 6.67-6.61(m, 1H), 6.40-6.39 (m, 2H), 6.23-6.19 (m, 1H), 4.81 (ABq, 2H), 4.53 (t,J=9.0 Hz, 2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 463.8 (M+1).

EXAMPLE 2.6 Synthesis of1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 138-139° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.46 (d, J=9.0 Hz, 2H), 7.35(d, J=9.0 Hz, 2H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (d, J=9.0Hz, 1H), 6.94-6.88 (m, 2H), 6.79 (d, J=9.0 Hz, 1H), 5.16-4.79 (m, 4H),3.78 (s, 3H), 2.45 (s, 3H); MS (ES+) m/z 412.9 (M+1).

EXAMPLE 2.7 Synthesis of1′-benzhydryl-6-(benzyloxy)-2H-spiro[benzofuran-3,3′-indolin]-2′-one

To a stirred solution of3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one(7.4 g, 14.8 mmol), chloroiodomethane (2.7 mL, 37.0 mmol) in anhydroustetrahydrofuran (200 mL) was added cesium carbonate (15.4 g, 47.4 mmol)under argon. The mixture was stirred at ambient temperature for 16 h,then filtered through a pad of celite. The filtrate was concentratedunder vacuum. The residue was purified by column chromatography (ethylacetate/hexanes, 1/5) followed by the treatment with diethylether/hexanes to afford1′-benzhydryl-6-(benzyloxy)-2H-spiro[benzofuran-3,3′-indolin]-2′-one(4.1 g, 55%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.42-7.25(m, 15H), 7.16-7.09 (m, 1H), 7.07-6.90 (m, 3H), 6.62-6.38 (m, 4H),5.03-4.90 (m, 3H), 4.73 (d, J=9.0 Hz, 1H); MS (ES+) m/z 510.1 (M+1).

EXAMPLE 2.8 Synthesis of1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.43-7.22 (m, 10H), 7.16-7.09 (m, 1H), 7.06-6.92 (m, 3H), 6.60 (d,J=6.8 Hz, 1H), 6.54-6.48 (m, 1H), 6.37 (d, J=10.0 Hz, 1H), 4.99 (d,J=9.0 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 3.85 (s, 3H); MS (ES+) m/z 452.1(M+1).

EXAMPLE 2.9 Synthesis of1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (56%) as a colorless solid: mp 182-184° C.; ¹H NMR (300MHz, CDCl₃) δ7.43-7.25 (m, 10H), 7.17-7.10 (m, 1H), 7.07-6.84 (m, 5H),6.56-6.49 (m, 1H), 6.39-6.32 (m, 1H), 5.01 (t, J=9.0 Hz, 2H), 4.74 (t,J=9.0 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.0, 159.3, 156.8, 156.1,141.7, 137.5, 137.2, 131.9, 130.3, 130.2, 128.8, 128.7, 128.6, 128.4,128.3, 128.1, 127.9, 123.8, 123.3, 116.5, 116.1, 112.4, 110.9, 110.8,110.6, 110.2, 80.3, 58.8, 58.0; MS (ES+) m/z 444.0 (M+23).

EXAMPLE 2.10 Synthesis of1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (74%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.42-7.27 (m, 10H), 7.16-6.92 (m, 4H), 6.59-6.49 (m, 3H), 6.37 (dd,J=8.4, 2.4 Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.75 (d, J=9.0 Hz, 1H), 3.77(s, 3H); MS (ES+) m/z 434.3 (M+1), 456.3 (M+23).

EXAMPLE 2.11 Synthesis of1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 183-185° C. (methanol); ¹HNMR (300 MHz, CDCl₃) δ7.41-7.28 (m, 10H), 7.15 (dd, J=6.8, 1.4 Hz, 1H),7.06 (s, 1H), 7.04-6.93 (m, 2H), 6.52-6.48 (m, 2H), 6.21 (s, 1H), 4.95(d, J=8.9 Hz, 1H), 4.69 (d, J=8.9 Hz, 1H), 4.22-4.17 (m, 2H), 4.15-4.10(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.3, 144.7, 141.8, 138.4,137.7, 137.5, 132.6, 128.83, 128.75, 128.5, 128.44, 128.36, 128.02,127.98, 123.9, 123.2, 121.5, 112.3, 111.6, 99.5, 80.4, 64.6, 64.0, 58.8,57.9; MS (ES+) m/z 462.3 (M+1).

EXAMPLE 2.12 Synthesis of1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-onewas obtained (70%) as an off-white solid: mp 208-211° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ7.41-7.29 (m, 10H), 7.16 (dd, J=6.6, 1.8 Hz, 1H),7.08 (s, 1H), 7.05-6.94 (m, 2H), 6.52 (d, J=7.8 Hz, 1H), 6.41 (s, 1H),6.28 (s, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.11 (dd,J=5.1, 5.1 Hz, 2H), 2.56 (t, J=6.3 Hz, 2H), 1.94-1.86 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ178.1, 160.1, 156.3, 141.8, 137.9, 137.5, 132.9,128.75, 128.73, 128.53, 128.52, 128.2, 128.00, 127.96, 132.9, 132.8,123.2, 121.3, 115.2, 112.3, 98.9, 80.3, 66.6, 58.8, 57.5, 24.8, 22.3; MS(ES+) m/z 460.1 (M+1).

EXAMPLE 2.13 Synthesis of1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(8-hydroxy-3,4-dihydro-2H-1,5-benzo-dioxepin-7-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (75%) as a pale pink solid: mp 165-168° C. (ethylacetate/methanol); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.28 (m, 10H), 7.15(dd, J=7.2, 1.4 Hz, 1H), 7.06 (s, 1H), 7.04-6.94 (m, 2H), 6.61 (s, 1H),6.50 (d, J=7.5 Hz, 1H), 6.35 (s, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d,J=9.0 Hz, 1H), 4.29-4.22 (m, 1H), 4.16-4.03 (m, 2H), 4.01-3.93 (m, 1H),2.24-2.01 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 156.9, 153.1, 146.4,141.8, 137.7, 137.6, 132.5, 128.9, 128.8, 128.6, 128.44, 128.41, 128.0,124.0, 123.4, 123.2, 116.1, 112.3, 103.6, 80.7, 70.92, 70.88, 58.8,57.8, 32.3; MS (ES+) m/z 476.1 (M+1).

EXAMPLE 2.14 Synthesis of1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 240-242° C.(dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ7.66 (d, J=7.2 Hz, 2H),7.45-7.29 (m, 9H), 7.11-6.97 (m, 4H), 6.89 (t, J=7.2 Hz, 1H), 6.46 (d,J=7.8 Hz, 1H), 6.01 (d, J=5.7 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H), 2.47 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.1, 164.5, 151.3, 146.2, 143.7, 138.6,138.0, 137.3, 129.9, 129.8, 129.0, 128.9, 128.8, 128.3, 128.0, 127.7,124.6, 122.8, 114.0, 112.7, 111.8, 110.7, 88.7, 75.8, 58.6, 14.8; MS(ES+) m/z 497.1 (M+39).

EXAMPLE 2.15 Synthesis of1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dionewas obtained (32%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.47-7.23 (m, 11H), 7.19-7.10 (m, 1H), 7.07-6.98 (m, 1H), 6.88 (s, 1H),6.72 (s, 1H), 6.64 (d, J=7.9 Hz, 1H), 6.20 (s, 1H), 4.93 (d, J=9.4 Hz,1H), 4.82 (d, J=9.4 Hz, 1H), 4.57 (s, 2H), 3.01 (s, 3H); MS (ES+) m/z489.0 (M+1).

EXAMPLE 2.16 Synthesis of1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dionewas obtained (40%) as a colorless solid: mp 228-229° C. (ethyl acetate);¹H NMR (300 MHz, CDCl₃) δ 7.42-7.28 (m, 10H), 7.15-6.96 (m, 4H), 6.60(s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.44 (s, 1H), 5.04 (d, J=9.0 Hz, 1H),4.77 (d, J=9.0 Hz, 1H), 3.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.6,157.7, 155.3, 142.0, 137.7, 137.4, 137.2, 133.2, 132.1, 129.0, 128.9,128.6, 128.5, 128.3, 128.2, 124.0, 123.5, 122.6, 112.6, 105.4, 92.0,80.6, 59.1, 58.0, 28.5; MS (ES+) m/z 475.1 (M+1).

EXAMPLE 2.17 Synthesis of1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using5-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dionewas obtained (65%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.47-7.28 (m, 11H), 7.18-7.11 (m, 2H), 7.06-6.99 (m, 1H), 6.89 (s, 1H),6.64 (d, J=7.9 Hz, 1H), 6.45 (s, 1H), 4.92 (d, J=9.4 Hz, 1H), 4.81 (d,J=9.4 Hz, 1H), 3.18 (s, 3H); MS (ES+) m/z 475.0 (M+1).

EXAMPLE 2.18 Synthesis of7′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,7′-chloro-1′-(diphenylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.45-7.06 (m, 14H), 6.38-6.32 (m, 2H), 4.75 (s, 2H), 4.48 (t, J=8.7 Hz,2H), 2.94 (t, J=8.7 Hz, 2H).

EXAMPLE 2.19 Synthesis of1′-(diphenylmethyl)-4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-7-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (89%) as a colorless solid: mp 81-82° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, DMSO-d₆) δ7.44-7.23 (m, 10H), 7.18-7.22 (m,1H), 6.94 (br s, 1H), 6.85-6.78 (m, 1H), 6.45 (s, 1H), 6.33 (s, 1H),4.83 (d, J=9.5 Hz, 1H), 4.69 (d, J=9.5 Hz, 1H), 4.52-4.50 (m, 2H),3.08-2.86 (m, 2H), 2.33 (br s, 3H); m/z 477.9 (M+1).

EXAMPLE 2.20 Synthesis of1′-(diphenylmethyl)-7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 183-184° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, DMSO-d₆) δ7.45-7.22 (m, 10H), 7.13-7.05 (m,3H), 6.98 (s, 1H), 6.44-6.43 (m, 2H), 4.91 (d, J=9.5 Hz, 1H), 4.80 (d,J=9.5 Hz, 1H), 4.51 (t, J=8.9 Hz, 2H), 2.97 (t, J=8.6 Hz, 2H); MS (ES+)m/z 463.9 (M+1).

EXAMPLE 2.21 Synthesis of6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(3-methylbutyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (67%): ¹H NMR (300 MHz, CDCl₃)

7.41-7.28 (m, 7H), 7.14-7.12 (m, 1H), 7.04-6.99 (m, 1H), 6.90-6.87 (m,1H), 6.59-6.55 (m, 1H), 6.44-6.30 (m, 1H), 5.00 (s, 2H), 4.79 (ABq, 2H),3.87-3.64 (m, 2H), 1.71-1.56 (m, 3H), 0.98 (d, J=6.0 Hz, 6H); MS (ES+)m/z 414.3 (M+1).

EXAMPLE 2.22 Synthesis of6-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(4-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-onewas obtained (78%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30(ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.16-7.03 (m, 3H), 6.69 (d, J=7.9 Hz,1H), 6.93 (dd, J=8.2, 1.8 Hz, 1H), 6.77-6.71 (m, 1H), 6.53 (d, J=8.2 Hz,1H), 6.42-6.37 (m, 1H), 5.06 (d, J=16.1 Hz, 1H), 4.97 (d, J=9.4 Hz, 1H),4.86 (d, J=16.1 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)δ176.5, 161.5, 151.8, 141.4, 131.6, 129.3, 128.0, 124.5 (d), 124.0,114.2, 112.6 (d), 109.2 (d), 80.1, 57.5, 36.9; MS (ES+) m/z 463.9 (M+1),465.9 (M+1).

EXAMPLE 2.23 Synthesis of5-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(5-bromo-2-hydroxyphenyl)-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,5-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-onewas obtained (78%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.36-7.27 (m, 2H), 7.17-6.98 (m, 3H), 6.8 (d, J=8.6 Hz, 1H), 6.78-6.72(m, 2H), 6.39 (d, J=3.4 Hz, 1H), 5.07-5.87 (m, 3H), 4.69 (d, J=9.1 Hz,1H); MS (ES+) m/z 463.9 (M+1), 465.9 (M+1).

EXAMPLE 2.24 Synthesis of6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-onewas obtained (17%) as a colorless solid: mp 169-171° C.; ¹H NMR (300MHz, CDCl₃) δ8.89 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz,1H), 6.59 (s, 1H), 6.21 (s, 1H), 4.84 (ABq, 2H), 4.30-4.17 (m, 2H),4.17-4.08 (m, 2H), 4.03-3.89 (m, 1H), 3.90-3.75 (m, 1H), 1.91-1.51 (m,3H), 1.04 (d, J=6.1 Hz, 6H); MS (ES+) m/z 423.1 (M+1).

EXAMPLE 2.25 Synthesis of6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[f-[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-onewas obtained (42%) as a colorless solid: mp 189-191° C.; ¹H NMR (300MHz, CDCl₃) δ6.77-6.73 (m, 1H), 6.72 (s, 1H), 6.52-6.45 (m, 2H),6.43-6.36 (m, 2H), 4.91 (ABq, 2H), 4.77 (ABq, 2H), 4.53 (t, J=8.6 Hz,2H), 4.27-4.14 (m, 4H), 3.10-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 161.8, 161.0, 151.9, 143.9, 140.1, 135.2, 124.9, 120.2, 120.0,118.8, 113.6, 112.6 (d, J=2.8 Hz, 10), 109.2, 98.8, 93.1, 80.4, 72.4,64.6, 64.0, 57.5, 37.0, 28.9; MS (ES+) m/z 485.9 (M+1).

EXAMPLE 2.26 Synthesis of6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-(((R)-tetrahydrofuran-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-onewas obtained (39%) as a colorless solid: mp 220-225° C.; ¹H NMR (300MHz, CDCl₃) δ6.65 (s, 1H), 6.64-6.60 (m, 1H), 6.51-6.46 (m, 1H), 6.36(s, 1H), 4.72 (dd, J=84.4, 8.9 Hz, 2H), 4.51 (dd, J=8.6, 8.6 Hz, 2H),4.25-4.19 (m, 2H), 4.19-4.13 (m, 2H), 3.94-3.82 (m, 2H), 3.80-3.67 (m,2H), 3.64-3.52 (m, 1H), 2.98 (t, J=8.6 Hz, 2H), 2.08-1.94 (m, 1H),1.94-1.80 (m, 2H), 1.74-1.60 (m, 1H); MS (ES+) m/z 421.9 (M+1).

EXAMPLE 2.27 Synthesis of6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-onewas obtained (76%) as a colorless solid: mp 176-178° C.; ¹H NMR (300MHz, CDCl₃) δ 6.75-6.67 (m, 2H), 6.49-6.43 (m, 2H), 6.37-6.31 (m, 1H),6.22-6.16 (m, 1H), 4.87 (ABq, 2H), 4.69 (ABq, 2H), 4.26-4.04 (m, 8H);¹³C NMR (75 MHz, CDCl₃ δ 177.2, 155.0, 152.0, 151.9, 144.6, 144.0,140.1, 138.3, 135.2, 124.3, 120.9, 113.7, 112.6, 112.6, 111.5, 109.1,99.3, 98.9, 80.0, 64.6, 64.5, 64.0, 63.9, 57.8, 37.0; MS (ES+) m/z 501.9(M+1).

EXAMPLE 2.28 Synthesis of1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-onetrifluoroacetate salt to replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onewas obtained. To a suspension of1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one(0.59 g, 1.3 mmol) in methanol (8.5 mL) was added 4 M hydrochloric acidin 1,4-dioxane (1.5 mL, 6.0 mmol) and the resulting solution was stirredat ambient temperature for 35 min. The solvent was removed and theresidue was dried under reduced pressure. The residue was thenprecipitated by addition of hexanes, sonicated and the solvent wasremoved under reduced pressure. This process was repeated several times,until the solid formed a fine suspension in hexanes. The material wasthen collected by filtration and air-dried to afford1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onehydrochloride (0.60 g, 94%) as a pale gray powder: mp 105° C. (dec.)(hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ7.33 (ddd, J=7.8, 7.5, 0.9 Hz,1H), 7.22-7.17 (m, 3H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.74 (d, J=3.3 Hz,1H), 6.48 (s, 1H), 6.25-6.19 (m, 1H), 5.10 (d, J=16.2 Hz, 1H), 5.02 (d,J=16.2 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3 Hz, 1H),4.33-4.22 (m, 2H), 3.27-3.18 (m, 2H), 2.68 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ176.4, 157.2, 153.2, 147.9, 141.9, 139.6 (q, J=42.0 Hz),131.3, 129.0, 123.9, 123.4, 121.5, 119.0 (q, J=267 Hz), 114.2 (q, J=2.8Hz), 112.4, 109.9, 109.3, 98.8, 79.9, 62.7, 57.1, 48.8, 48.6, 41.5,36.6; MS (ES+) m/z 457.1 (M+1); Anal. Calcd. for C₂₄H₁₉FN₂O₄.HCl: C,58.49; H, 4.09; N, 5.68. Found: C, 58.85; H, 3.74; N, 5.37.

EXAMPLE 2.29 Synthesis of1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate to replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid. Following the proceduredescribed in EXAMPLE 2.28 and making non-critical variations using1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-oneto replace1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one,1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H-spiro[furo-[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onehydrochloride was obtained (83%) as a colorless solid: mp>135° C. (dec.)(hexanes); ¹H NMR (300 MHz, DMSO-d₆) (diastereomers) δ7.83 (br s, 1H),7.36-7.29 (m, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H),7.07-7.00 (m, 1H), 6.51 (br s, 1H), 6.44, 6.40 (br s, 1H), 4.82-4.59 (m,2H), 4.38-4.26 (m, 2H), 4.25-4.14 (m, 1H), 3.87-3.69 (m, 3H), 3.66-3.59(m, 1H), 3.36-3.24 (m, 2H), 2.78, 2.75 (br s, 3H), 2.02-1.72 (m, 3H),1.68-1.55 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) (diastereomers) δ 176.8,158.2, 157.8, 148.3, 143.1, 142.9, 131.5, 131.2, 128.9, 128.8, 123.6,123.5, 122.9, 122.3, 114.0, 113.3, 109.9, 109.8, 98.9, 79.9, 79.8, 75.7,75.6, 67.3, 62.3, 57.0, 48.9, 43.9, 43.7, 42.3, 42.1, 28.7, 28.5, 25.2,25.1; MS (ES+) m/z 393.1 (M+1).

EXAMPLE 2.30 Synthesis of4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(6-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-onetrifluoroacetate to replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-onewas obtained (62%) as a pale yellow solid: mp 138-140° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ 7.26 (dd,J=7.7, 7.7 Hz, 1H), 7.16-6.99 (m, 3H), 6.29 (s, 1H), 6.122, 6.117 (s,1H), 4.86 (d, J=8.9 Hz, 1H), 4.61 (d, J=8.9 Hz, 1H), 4.31-4.21 (m, 1H),4.13 (dd, J=4.5, 4.5 Hz, 2H), 3.99-3.66 (m, 4H), 3.23 (dd, J=4.5, 4.2Hz, 2H), 2.87 (s, 3H), 2.07-1.83 (m, 3H), 1.81-1.67 (m, 1H); ¹³C NMR (75MHz, CDCl₃) (diastereomers) δ178.5, 178.3, 156.1, 143.1, 142.9, 139.0,137.8, 132.7, 132.6, 128.7, 128.6, 123.84, 123.76, 123.2, 116.41,116.35, 110.26, 110.22, 109.7, 109.4, 94.4, 80.2, 80.1, 77.3, 76.8,68.38, 68.35, 64.5, 58.3, 49.2, 44.64, 44.58, 39.0, 29.4, 29.0, 25.9,25.7; MS (ES+) m/z 393.0 (M+1).

EXAMPLE 2.31 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-onewas obtained (3%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.38-6.99 (m, 4H), 6.47 (s, 1H), 6.30 (d, J=3.6 Hz, 1H), 5.15 (ABq, 2H),4.89 (d, J=9.0 Hz, 1H), 4.71-4.61 (m, 3H), 4.30-4.20 (m, 1H), 3.96-3.64(m, 4H), 2.10-1.60 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 177.8,160.5, 160.5, 153.9, 142.8, 142.7, 132.3, 132.2, 128.8 (2C), 123.6,123.3, 122.4, 122.3, 119.6 (2C), 113.9, 109.6, 109.5, 99.2, 91.2, 80.3,76.9, 68.2, 68.1, 66.2, 57.5 (2C), 44.7, 44.6, 29.2, 29.0, 25.6, 25.5;MS (ES+) m/z 379.9 (M+1), 401.8 (M+23).

EXAMPLE 2.32 Synthesis of1′-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one

A suspension of1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one(5.1 g, 11.8 mmol), 1,2-dibromoethane (4.7 g, 25.0 mmol) and cesiumcarbonate (24.4 g, 75.0 mmol) in tetrahydrofuran (200 mL) was stirredunder argon at ambient temperature for 16 h and at 50° C. for 7 h. Thereaction mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was subjected to column chromatographywith dichlormethane/methanol (100/1-20/1) to afford1′-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one(2.11 g, 39%) as a colorless solid: MS (ES+) m/z 459.8 (M+1).

EXAMPLE 2.33 Synthesis of1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-7-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%) as a colorless solid: MS (ES+) m/z 479.9 (M+1).

EXAMPLE 2.34 Synthesis of2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (55%) as an off-white solid: mp 59-60° C. (recrystallizedfrom the melt); ¹H NMR (300 MHz, CDCl₃) δ7.37-7.30 (m, 1H), 7.21-7.15(m, 1H), 7.14-7.07 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.79-6.74 (m, 1H),6.72 (s, 1H), 6.44-6.40 (m, 1H), 6.36 (s, 1H), 5.12-4.83 (m, 3H), 4.73(d, J=9.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 176.7, 157.0, 151.8, 144.7,142.2, 141.7, 141.5, 138.5, 135.4, 132.0, 131.4, 129.6, 128.6, 124.2,122.4, 120.7, 117.1, 112.8, 109.6, 109.3, 104.6, 94.4, 80.6, 58.0, 37.1;MS (ES+) m/z 465.7 (M+1).

EXAMPLE 2.35 Synthesis of2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-methyl-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(10%) was obtained as a pale yellow solid: mp 176-178° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.39-7.32 (m, 1H), 7.18-7.05 (m, 2H),6.92 (d, J=7.8 Hz, 1H), 6.72 (s, 1H), 6.40 (s, 1H), 4.96 (d, J=9.1 Hz,1H), 4.70 (d, J=9.1 Hz, 1H), 3.29 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)δ177.0, 157.1, 144.7, 143.1, 138.4, 132.0, 131.7, 129.5, 124.0, 123.8,122.5, 108.7, 104.8, 94.4, 80.8, 58.2, 26.9; MS (ES+) m/z 331.9 (M+1).

EXAMPLE 2.36 Synthesis of2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (23%) as a colorless solid: mp 200-201° C. (ether/hexanes);¹H NMR (300 MHz, acetone-d₆) δ8.75 (d, J=4.1 Hz, 1H), 8.24 (d, J=7.9 Hz,1H), 7.62-7.55 (m, 1H), 7.30-7.22 (m, 2H), 7.10-6.84 (m, 4H), 5.42 (d,J=17.4 Hz, 1H), 5.22 (d, J=17.4 Hz, 1H), 5.01 (d, J=9.2 Hz, 1H), 4.91(d, J=9.2 Hz, 1H); ¹³C NMR (75 MHz, acetone-d₆) δ177.6, 158.1, 153.5,153.4, 144.9, 144.0, 138.6, 135.7, 132.8, 129.9, 126.9, 125.3, 124.9,124.6, 124.0, 123.7, 123.3, 109.9, 106.6, 98.4, 81.3, 58.7, 42.9; MS(ES+) m/z 477.0 (M+1).

EXAMPLE 2.37 Synthesis of6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using6-(diphenylmethyl)-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-onewas obtained (67%) as a colorless solid: MS (ES+) m/z 504.0 (M+1).

EXAMPLE 2.38 Synthesis of3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-onewas obtained (9%) as a yellow solid: mp 169-170° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.75 (s, 1H), 8.10 (m, 1H), 7.92 (m, 1H), 7.43-7.28 (m, 4H),6.92-6.86 (m, 2H), 6.51 (s, 1H), 6.44 (s, 1H), 5.17-5.06 (m, 2H),4.97-4.88 (m, 2H), 4.58-4.49 (m, 2H), 3.79 (s, 3H), 3.09-2.82 (m, 2H);¹³C NMR (75 MHz, CDCl₃) δ 179.1, 162.2, 161.0, 159.3, 148.0, 144.6,140.2, 130.9, 128.8, 127.8, 127.6, 124.8, 122.4, 120.4, 119.8, 118.9,114.4, 113.9, 93.4, 79.6, 72.4, 58.5, 55.3, 43.9, 29.0; MS (ES+) m/z451.0 (M+1).

EXAMPLE 2.39 Synthesis of6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

To a stirred solution of2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(9.40 g, 24.3 mmol) and chloroiodomethane (4.40 mL, 60.4 mmol) intetrahydrofuran (250 mL) was added cesium carbonate (23.8 g, 73.0 mmol)under nitrogen. The reaction mixture was stirred at ambient temperaturefor 20 h and 5% w/v hydrochloric acid was added. The mixture wasextracted with ethyl acetate (3×200 mL). The combined organic extractswere washed with water and brine, and dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography and eluted with ethylacetate to afford6-hydroxy-1-(4-methoxybenzyl)-2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(2.57 g, 26%): mp 112-114° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 11.32 (s, 1H), 7.29-7.16 (m, 4H), 7.02-6.97 (m, 2H),6.89-6.85 (m, 3H), 6.54 (s, 1H), 4.93-4.77 (m, 4H), 3.68 (s, 3H); MS(ES+) m/z 398.8 (M+1).

EXAMPLE 2.40 Synthesis of6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

To a stirred solution of2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile(10.50 g, 27.03 mmol) and chloroiodomethane (5.00 mL, 68.7 mmol) intetrahydrofuran (200 mL) and N,N-dimethylformamide (50 mL) was addedcesium carbonate (26.40 g, 81.02 mmol) under nitrogen. The reactionmixture was stirred at ambient temperature for 20 h and filtered througha pad of diatomaceous earth. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography and eluted with ethylacetate/hexanes (1/3) to afford6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(5.27 g, 48%): mp 142-143° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.29-7.23 (m,3H), 7.11-7.02 (m, 2H), 6.89-6.85 (m, 4H), 6.77 (d, J=9.0 Hz, 1H),5.12-4.75 (m, 4H), 3.78 (s, 3H); MS (ES+) m/z 400.7 (M+1).

EXAMPLE 2.41 Synthesis of1′-(4-methoxybenzyl)-3-methylspiro[furo[2,3-f][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(4-methoxybenzyl)-3-methylspiro[furo[2,3-f][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-onewas obtained (17%): mp 183-184° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.29-7.21 (m, 3H), 7.13-7.10 (m, 1H), 7.05 (s, 1H),7.03-6.98 (m, 1H), 6.89-6.86 (m, 3H), 6.82 (s, 1H), 5.07-5.00 (m, 2H),4.79-4.74 (m, 2H), 3.78 (s, 3H), 2.51 (s, 3H); MS (ES+) m/z 412.8 (M+1).

EXAMPLE 2.42 Synthesis of4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (66%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.47-7.16 (m, 12H), 6.85 (s, 1H), 6.82-6.76 (m, 1H), 6.57 (s, 1H), 5.92(s, 1H), 5.66 (ABq, 2H), 4.22-4.14 (m, 4H).

EXAMPLE 2.43 Synthesis of4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.40 and makingnon-critical variations using4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-oneto replace2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile,4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′N)-onewas obtained (95%): ¹H NMR (300 MHz, CDCl₃) δ 7.23-7.14 (m, 2H),6.87-6.79 (m, 1H), 6.43 (s, 1H), 6.16 (s, 1H), 4.93 (ABq, 2H), 4.22-4.07(m, 4H), 3.24 (s, 3H); MS (ES+) m/z 387.9 (M+1), 389.9 (M+1).

EXAMPLE 2.44 Synthesis of1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: mp 196-198° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.46-7.26 (m, 10H), 7.19 (ddd, J=8.2, 8.2, 6.1 Hz, 1H),6.89 (s, 1H), 6.83 (dd, J=8.9, 8.9 Hz, 1H), 6.50 (s, 1H), 6.46 (d, J=8.0Hz, 1H), 6.09 (s, 1H), 4.83 (q, J=9.6 Hz, 2H), 4.14 (dd, J=5.3, 3.2 Hz,4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 157.9 (d, ¹J_(C-F)=247 Hz),144.3, 143.8 (d, ³J_(C-F)=8.4 Hz), 137.2 (d, ³J_(C-F)=13.6 Hz), 130.5(d, ³J_(C-F)=8.6 Hz), 128.1, 127.8 (d, ³J_(C-F)=9.0 Hz), 119.2, 117.3(d, ²J_(C-F)=19.0 Hz), 110.4, 110.0 (d, ²J_(C-F)=19.7 Hz), 107.8 (d,⁴J_(C-F)=2.8 Hz), 98.7, 77.5, 64.1, 63.5, 58.6, 55.8 (d, ⁴J_(C-F)=2.8Hz); MS (ES+) m/z 480.0 (M+1),

EXAMPLE 2.45 Synthesis of1′-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(4-fluorophenyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 210-212° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.63-7.59 (m, 2H), 7.45-7.39 (m, 2H), 7.31-7.23 (m, 2H),7.10 (dd, J=7.3, 7.3 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.46(s, 1H), 4.80 (q, J=9.4 Hz, 2H), 4.21-4.09 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.1, 161.2 (d, ¹J_(C-F)=245 Hz), 154.6, 144.1, 143.0,137.7, 131.6, 130.4 (d, ⁴J_(C-F)=2.9 Hz), 129.4 (d, ³J_(C-F)=8.9 Hz),128.6, 123.7, 123.3, 121.1, 116.4 (d, ²J_(C-F)=22.8 Hz), 111.5, 109.0,98.6, 79.6, 64.1, 63.5, 57.2; MS (ES+) m/z 390.0 (M+1).

EXAMPLE 2.46 Synthesis of1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 10 mL microwave reaction vessel was charged with4′-bromo-1-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.38 g, 1.40 mmol), tetrakis(triphenylphosphine)palladium (0.080 g,0.14 mmol), quinolin-3-ylboronic acid (0.20 g, 2.3 mmol), 2 M aqueoussodium carbonate (1.8 mL) and N,N-dimethylformamide (3.mL). The reactionmixture was irradiated at 150° C. for 15 min in a microwave reactor. Thereaction was repeated and both reaction mixtures were combined, pouredinto distilled water (75 mL) and extracted with ethyl acetate (150 mL).The combined organic extracts were washed with water (3×50 mL) and brine(100 mL), dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography and eluted witha 20% to 50% gradient of ethyl acetate in hexanes to afford1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.29 g, 35%) as a light yellow solid: MS (ES+) m/z 589.0 (M+1).

EXAMPLE 2.47 Synthesis of1′-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 4-phenoxyphenylboronic acid to replacequinolin-3-ylboronic acid,1-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (99%) as a colorless solid: MS (ES+) m/z 630.0 (M+1).

EXAMPLE 2.48 Synthesis of1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile

A 10 mL microwave reaction vessel was charged with6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.51 g, 1.1 mmol), nickel chloride hexahydrate (0.25 g, 1.1 mmol),sodium cyanide (0.10 g, 2.1 mmol) and 1-methyl-2-pyrrolidinone (1 mL).The solution was irradiated at 200° C. for 20 min in a microwavereactor. The solution was allowed to cool to ambient temperature,diluted with ethyl acetate (25 mL) and filtered. The filtrate was washedwith brine (3×15 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 15% to 50% gradient of ethyl acetate in hexanes toafford1′-(diphenylmethyl)-2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile(0.50 g, 100%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)

7.44-7.22 (m, 10H), 7.21-7.18 (m, 1H), 7.14-6.93 (m, 5H), 6.72 (d, J=7.8Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.80 (d, J=9.2Hz, 1H).

EXAMPLE 2.49 Synthesis of5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one(2.00 g, 4.40 mmol) in anhydrous N,N-dimethylformamide (25 mL) was addedcesium carbonate (4.30 g, 13.2 mmol) and chloroiodomethane (0.85 g, 4.9mmol). The solution was stirred at ambient temperature for 16 h andpoured into water (100 mL). The mixture was extracted with ethyl acetate(3×50 mL) and the combined ethyl acetate extracts were washed with brine(2×35 mL), dried over magnesium sulfate, filtered and concentrated invacuo. The residue was triturated in dichloromethane/diethyl ether (2/5,14 mL) to afford5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.44 g, 72%) as a beige solid: mp>250° C. (dichloromethane/diethylether); ¹H NMR (300 MHz, CDCl₃)

8.57-8.52 (m, 1H), 7.69-7.61 (m, 1H), 7.33-7.27 (m, 3H), 7.26-7.16 (m,1H), 6.77 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.16 (d, J=15.8Hz, 1H), 4.97-4.87 (m, 2H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ 176.9, 155.2, 155.1, 149.6, 144.9, 141.1,138.4, 137.2, 134.2, 131.7, 127.0, 122.9, 121.7, 120.4, 116.1, 111.7,111.1, 99.5, 80.0, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 465.0 (M+1),467.0 (M+1).

EXAMPLE 2.50 Synthesis of2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile

Following the procedure as described in EXAMPLE 2.48 and makingnon-critical variations using5′-bromo-1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5-carbonitrilewas obtained (83%) as a colorless solid: mp 198-199° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.56-8.52 (m, 1H), 7.65-7.68(m, 1H), 7.51 (dd, J=8.2, 1.4 Hz, 1H), 7.40-7.38 (m, 1H), 7.30-7.18 (m,2H), 7.01 (d, J=8.2 Hz, 1H), 6.51 (s, 1H), 6.29 (s, 1H), 5.20 (d, J=15.8Hz, 1H), 4.96 (d, J=15.5 Hz, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.64 (d, J=9.1Hz, 1H), 4.23-4.09 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.1, 155.2,154.4, 149.7, 146.0, 145.1, 138.6, 137.2, 133.9, 133.4, 127.2, 123.1,122.0, 119.8, 118.7, 111.6, 110.2, 106.7, 99.7, 79.8, 64.5, 63.9, 57.8,46.1; MS (ES+) m/z 412.0 (M+1).

EXAMPLE 2.51 Synthesis of5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using5-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (76%) as a colorless solid: MS (ES+) m/z 539.9 (M+1), 541.1(M+1).

EXAMPLE 2.52 Synthesis of1′-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a 10 mL reaction vessel was added tri-o-tolylphosphine (0.022 g,0.075 mmol), palladium acetate trimer (0.013 g, 0.020 mmol),triethylamine (0.13 g, 1.30 mmol), N,N-dimethylformamide (1.5 mL),tetramethyltin (0.20 g, 1.1 mmol) and1′-(diphenylmethyl)-5′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.50 g, 0.93 mmol). The reaction vessel was sealed, heated at 110° C.for 16 h, allowed to cool to ambient temperature and poured into water(50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and thecombined organic extracts were washed with brine (2×50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography and eluted with 15% ethyl acetate inhexanes followed by recrystallization from diethyl ether to afford1′-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.38 g, 86%) as a colorless solid: MS (ES+) m/z 476.0 (M+1).

EXAMPLE 2.53 Synthesis of phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate

To a high pressure steel reaction vessel were added4′-bromo-1-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(10 g, 26 mmol), palladium acetate (0.35 g, 1.55 mmol),1,3-bis(dicyclohexylphosphonium)propane bis(tetrafluoroborate) (0.64 g,1.0 mmol), phenol (2.92 g, 31.0 mmol), potassium carbonate (5.34 g, 39.8mmol), activated 4 Å molecular sieves (4.00 g) and N,N-dimethylformamide(30.0 mL). The reaction vessel was purged with nitrogen for 10 min,sealed, pressurized with carbon monoxide to 150 psi and stirred at 120°C. for 82 h. The mixture was poured into water (100 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith brine (2×50 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 15% to 75% gradient of ethyl acetate in hexanesfollowed by recrystallization form dichloromethane/diethyl ether toafford phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate(3.30 g, 30%) as a colorless solid: mp 184-186° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃)

7.85 (d, J=8.0 Hz, 1H), 7.49 (dd, J=7.9, 7.9 Hz, 1H), 7.35-7.11 (m, 4H),6.84-6.78 (m, 2H), 6.24 (s, 1H), 6.12 (s, 1H), 5.11 (d, J=8.5 Hz, 1H),4.87 (d, J=8.5 Hz, 1H), 4.18-4.05 (m, 4H), 3.29 (s, 3H); MS (ES+) m/z451.92 (M+23).

EXAMPLE 2.54 Synthesis of1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4-dioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1′H)-one

A 100 mL flask was charged under argon with3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-{[3-(trifluoromethyl)pyridine-2-yl]methyl}-1,3-dihydro-2H-indol-2-one(0.46 g, 1.0 mmol), chloroiodomethane (0.36 g, 2.0 mmol), cesiumcarbonate (1.3 g, 4.0 mmol) and anhydrous tetrahydrofuran (50 mL). Thereaction mixture was heated at reflux for 3 h, allowed to cool toambient temperature and filtered. The filtrate was concentrated in vacuoand the residue was purified by column chromatography and eluted with a0% to 50% gradient of ethyl acetate in dichloromethane to afford1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4-dioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1′H)-one(0.16 g, 34%) as an off-white solid: mp>250° C. (methanol); ¹H NMR (300MHz, CDCl₃) δ 8.65 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.35-7.14(m, 3H), 6.95-7.03 (m, 1H), 6.68 (s, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.52(s, 1H), 5.70 (ABq, 2H), 5.21 (ABq, 2H), 4.25-4.01 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 176.3, 152.3, 152.2, 147.8, 144.1, 143.3, 138.9, 134.3,134.2, 134.2, 134.1, 130.7, 130.2, 129.2, 125.6, 125.2, 124.8, 124.4,124.0, 123.5, 122.2, 122.0, 114.9, 114.2, 108.7, 105.3, 88.3, 77.2,64.5, 64.0, 41.8, 41.7.

EXAMPLE 2.55 Synthesis of1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as an off-white solid: MS (ES+) m/z 479.8 (M+1).

EXAMPLE 2.56 Synthesis of1-(diphenylmethyl)-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-onewas obtained (93%) as an off-white solid: MS (ES+) m/z 460.0 (M+1).

EXAMPLE 2.57 Synthesis of1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-hydroxy-1-benzothiophen-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-onewas obtained (54%) as an off-white solid: MS (ES+) m/z 460.2 (M+1).

EXAMPLE 2.58 Synthesis of1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one5,5′-dioxide

To a solution of1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one(1.12 g, 2.44 mmol) in dichloromethane (50 mL) at ambient temperaturewas added 3-chloroperbenzoic acid (77% w/w, 0.65 g, 2.9 mmol) and themixture was stirred for 16 h. The reaction mixture was diluted withdichloromethane (100 mL), washed with saturated aqueous sodiumbicarbonate (3×150 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 0% to 20% gradient of ethyl acetate in dichloromethaneto afford1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one5,5′-dioxide (0.98 g, 82%) as an off-white solid: MS (ES+) m/z 492.0(M+1).

EXAMPLE 2.59 Synthesis of1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-onewas obtained (50%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.82(d, J=9.6 Hz, 1H), 7.58-6.92 (m, 15H), 6.55 (d, J=7.8 Hz, 1H), 5.25 (d,J=9.3 Hz, 1H), 4.99 (d, J=9.3 Hz, 1H); MS (ES+) m/z 446 (M+1).

EXAMPLE 2.60 Synthesis of6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.40 and makingnon-critical variations using3-(7-chloro-6-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneto replace2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile,6-chloro-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.42-7.26 (m, 10H), 7.20-7.15 (m, 1H), 7.11 (s, 1H), 7.03-6.95 (m, 2H),6.78 (s, 1H), 6.50-6.45 (m, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.76 (d, J=8.7Hz, 1H), 4.12-3.84 (m, 4H); MS (ES+) m/z 496.2 (M+1).

EXAMPLE 2.61 Synthesis of1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 213-216° C.; ¹H NMR (300MHz, CDCl₃) δ 7.41-7.26 (m, 10H), 7.15-7.12 (m, 1H), 7.08-6.97 (m, 3H),6.78 (dd, J=10.5, 6.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (dd, J=9.0,7.8 Hz, 1H), 5.03 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H); ¹³C NMR (75MHz, CDCl₃) δ 176.8, 156.6 (d, J=11.0 Hz), 151.2 (dd, J_(C-F)=248.2,14.5 Hz), 145.6 (dd, J_(C-F)=241.5, 13.9 Hz), 141.7, 137.4, 137.1,131.5, 128.8, 128.8, 128.7, 128.3, 128.3, 128.1, 128.0, 124.2 (dd,J=6.4, 3.3 Hz), 123.8, 123.3, 112.4, 111.5 (dd, J=20.4, 1.6 Hz), 100.1(d, J=22.4), 80.8, 58.9, 57.5; MS (ES+) m/z 440.2 (M+1).

EXAMPLE 2.62 Synthesis of1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-onewas obtained (81%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.37-7.32 (m, 10H), 7.17-7.14 (m, 1H), 7.07 (s, 1H), 7.05-6.94 (m, 2H),6.67 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.96 (d, J=8.9 Hz,1H), 4.69 (d, J=8.9 Hz, 1H), 2.73 (br s, 2H), 2.54 (br s, 1H), 1.72-1.70(m, 4H); MS (ES+) m/z 457.9 (M+1).

EXAMPLE 2.63 Synthesis of4′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,5-dimethoxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,4′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (77%): mp 62-65° C.; ¹H NMR (300 MHz, CDCl₃) δ6.80 (d,J=8.4 Hz, 1H), 6.74-6.69 (m, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.45 (s, 1H),6.38-6.32 (m, 1H), 6.20 (s, 1H), 4.90 (ABq, 2H), 4.85-4.81 (m, 2H),4.18-4.05 (m, 4H), 3.78 (s, 3H), 3.40 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.0, 155.6, 152.3, 152.2, 149.9, 146.6, 144.6, 137.9, 135.1, 125.0,120.3, 112.7, 111.1, 109.2, 103.7, 99.1, 78.2, 64.5, 63.9, 60.4, 57.7,56.3, 37.1; MS (ES+) m/z 503.9 (M+1).

EXAMPLE 2.64 Synthesis of4′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,7-dimethoxy-1-[2-(2-methoxyethoxy)ethyl]-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,4′,7-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (24%): mp 109-110° C.; ¹H NMR (300 MHz, CDCl₃) δ6.80 (d,J=9.0 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 6.24 (s, 1H), 4.76(ABq, 2H), 4.26-4.03 (m, 6H), 3.81 (s, 3H), 3.77-3.69 (m, 2H), 3.64-3.59(m, 2H), 3.59 (s, 3H), 3.49-3.43 (m, 2H), 3.31 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ178.4, 155.6, 150.4, 144.1, 139.7, 137.6, 131.0, 120.2, 119.5,113.4, 111.1, 106.1, 98.7, 71.9, 69.8, 68.8, 64.5, 63.8, 59.0, 57.5,56.4, 56.0, 41.2; MS (ES+) m/z 457.9 (M+1).

EXAMPLE 2.65 Synthesis of6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-[2-(2-methoxyethoxy)ethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-onewas obtained (74%): mp 146-148° C.; ¹H NMR (300 MHz, CDCl₃) δ6.64 (s,1H), 6.56 (s, 1H), 6.43 (s, 1H), 6.22 (s, 1H), 4.67 (ABq, 2H), 4.27-4.03(m, 8H), 3.98-3.65 (m, 4H), 3.65-3.55 (m, 2H), 3.52-3.45 (m, 2H), 3.34(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 155.0, 144.4, 143.8, 139.6,138.2, 136.4, 124.7, 121.4, 113.3, 111.5, 99.3, 99.2, 80.1, 71.9, 70.4,68.1, 64.6, 64.5, 64.1, 63.9, 59.0, 57.8, 40.3; MS (ES+) m/z 455.9(M+1).

EXAMPLE 2.66 Synthesis of6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using8-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-methoxybenzyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-onewas obtained (80%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.76(s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.05 (d, J=8.5Hz, 1H), 6.88 (d, J=8.6 Hz, 2H), 6.58 (s, 1H), 6.21 (s, 1H), 4.99 (ABq,2H), 4.86 (ABq, 2H), 4.25-4.04 (m, 4H), 3.79 (s, 3H); MS (ES+) m/z 473.1(M+1).

EXAMPLE 2.67 Synthesis of1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of6-(benzyloxy)-1-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.22 g, 0.44 mmol) in dichloromethane (3 mL) at ambient temperature wasadded iodotrimethylsilane (0.12 g, 0.61 mmol). The mixture was stirredat ambient temperature for 3 h and concentrated in vacuo. The residuewas purified by column chromatography to afford1-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.25 g, 67%): ¹H NMR (300 MHz, CDCl₃) δ7.46-7.25 (m, 10H), 7.17-7.09(m, 1H), 7.08-7.02 (m, 1H), 7.02-6.91 (m, 2H), 6.57-6.37 (m, 2H), 6.32(s, 1H), 6.24-6.12 (m, 1H), 5.70 (s, 1H), 4.85 (ABq, 2H).

EXAMPLE 2.68 Synthesis of1′-(diphenylmethyl)-6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.9 g, 6.9 mmol) in anhydrous N,N-dimethylformamide (30 mL) was addedat ambient temperature potassium carbonate (2.9 g, 21 mmol). The mixturewas stirred at ambient temperature for 10 min and 2-bromoethyl methylether (1.9 g, 14 mmol) was added. The mixture was stirred at 40° C. for7 h, allowed to cool to ambient temperature and poured into water (300mL), causing a precipitate to be deposited.

The solid was collected by filtration to afford1′-(diphenylmethyl)-6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(2.84 g, 85%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.46-7.22(m, 10H), 7.16-7.10 (m, 1H), 7.06 (s, 1H), 7.03-6.92 (m, 2H), 6.89-6.74(m, 2H), 6.57-6.45 (m, 1H), 6.30-6.23 (m, 1H), 4.85 (ABq, 2H), 3.92-3.87(m, 2H), 3.72-3.55 (m, 2H), 3.39 (s, 3H).

EXAMPLE 2.69 Synthesis of5-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,5-(benzyloxy)-1-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (88%): ¹H NMR (300 MHz, CDCl₃) δ7.43-7.26 (m, 15H),7.17-7.10 (m, 1H), 7.06 (s, 1H), 7.05-6.91 (m, 2H), 6.90-6.76 (m, 2H),6.55-6.46 (m, 1H), 6.30-6.23 (m, 1H), 4.85 (ABq, 2H), 4.79 (s, 2H).

EXAMPLE 2.70 Synthesis of1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.68 and makingnon-critical variations using5-(benzyloxy)-1-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1′-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (78%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.22(br s, 1H), 7.30-7.08 (m, 10H), 7.02-6.93 (m, 1H), 6.88 (s, 1H),6.85-6.75 (m, 2H), 6.65-6.49 (m, 2H), 6.38-6.26 (m, 1H), 6.13-6.02 (m,1H), 4.65 (ABq, 2H).

EXAMPLE 2.71 Synthesis of1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.68 and makingnon-critical variations using1-(diphenylmethyl)-5-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1′-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (90%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.44-7.25 (m, 10H), 7.15-7.07 (m, 1H), 7.04 (s, 1H), 7.00-6.90 (m, 2H),6.58-6.44 (m, 3H), 6.41-6.33 (m, 1H), 4.86 (ABq, 2H), 4.15-3.98 (m, 2H),3.75-3.66 (m, 2H), 3.41 (s, 3H).

EXAMPLE 2.72 Synthesis of1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(5-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-onewas obtained (85%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.47-7.22 (m, 12H), 7.10 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 6.99 (dd,J=7.4, 7.4 Hz, 1H), 6.88 (s, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.32 (d, J=8.3Hz, 1H), 6.04 (d, J=8.3 Hz, 1H), 4.93 (d, J=9.5 Hz, 1H), 4.81 (d, J=9.5Hz, 1H), 4.27 (s, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.8, 148.8, 144.7,142.0, 137.6, 137.5, 131.6, 129.3, 128.7, 128.5, 128.3, 128.1, 127.9,127.7, 127.6, 123.9, 122.9, 122.4, 113.8, 111.0, 109.9, 80.1, 64.1,63.9, 58.1, 57.1; MS (ES+) m/z 461.9 (M+1).

EXAMPLE 2.73 Synthesis of1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2 and makingnon-critical variations using1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-4,6-dimethoxy-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one,1-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (96%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.41-7.24 (m, 10H), 6.97 (s, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 6.04 (d,J=1.8 Hz, 1H), 5.69 (d, J=1.8 Hz, 1H), 4.81 (ABq, 2H), 4.21-4.06 (m,4H), 3.62 (s, 3H), 3.47 (s, 3H); MS (ES+) m/z 522.1 (M+1).

EXAMPLE 2.74 Synthesis of1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.40 and makingnon-critical variations using1-(diphenylmethyl)-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-oneto replace2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile,1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-onewas obtained (34%): ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J=1.5 Hz, 1H),8.46 (d, J=1.5 Hz, 1H), 8.07-8.04 (m, 1H), 7.63-6.86 (m, 15H), 6.55-6.52(m, 1H), 5.10 (ABq, 2H).

EXAMPLE 3 Synthesis of6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A stirred solution of1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(7.2 g, 16.1 mmol), triethylsilane (15 mL) and trifluoroacetic acid (50mL) was refluxed for 14 h. The solution was concentrated in vacuo andprecipitated from hexanes to afford6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.9 g,86%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.54(s, 1H), 7.23-7.14 (m, 1H), 7.03 (d, J=6.9 Hz, 1H), 6.95-6.86 (m, 2H),6.58 (s, 1H), 6.41 (s, 1H), 4.68 (ABq, 2H), 3.73 (s, 3H), 1.91 (s, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1,124.4, 124.2, 122.7, 120.3, 118.5, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0;MS (ES+) m/z 282.2 (M+1).

EXAMPLE 3.1 Synthesis of4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp>200° C.; ¹H NMR (300 MHz,DMSO-d₆) δ10.80 (s, 1H), 7.23 (dd, J=8.0, 8.0 Hz, 1H), 6.93 (d, J=8.0Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 6.49 (s, 1H), 6.31 (s, 1H), 4.84 (d,J=9.6 Hz, 1H), 4.68 (d, J=9.6 Hz, 1H), 4.46 (t, J=8.7, Hz, 2H), 2.92 (t,J=8.6 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ182.8, 166.0, 165.8, 148.3,134.9, 134.3, 133.8, 127.1, 123.9, 123.2, 122.4, 113.4, 96.5, 81.8,76.6, 62.4, 32.9; MS (ES+) m/z 313.9 (M+1), 315.9 (M+1).

EXAMPLE 3.2 Synthesis of6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (89%) asa colorless solid: MS (ES+) m/z 316.1 (M+1), 318.1 (M+1).

EXAMPLE 3.3 Synthesis of5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained(88%) as a colorless solid: mp 206-207° C. (ethyl acetate/hexanes); ¹HNMR (300 MHz, DMSO-d₆) δ10.5 (s, 1H), 7.23-7.18 (m, 1H), 7.03-7.01 (m,1H), 6.94-6.88 (m, 2H), 6.73 (s, 1H), 6.43 (s, 1H), 4.68 (ABq, 2H), 2.13(s, 3H), 1.99 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.9, 159.1, 142.2,138.0, 133.3, 129.1, 127.0, 124.2, 124.1, 122.7, 111.2, 110.2, 79.5,58.2, 20.2, 19.1; MS (ES+) m/z 266.3 (M+1).

EXAMPLE 3.4 Synthesis of5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]furan-3,3′-indol]-2′(1′H)-onewas obtained (91%) as a colorless solid: mp 257-259° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ10.35 (s, 1H), 6.86-6.73 (m, 3H), 6.43 (s, 1H),6.22 (s, 1H), 4.64 (ABq, 2H), 4.43 (t, J=9.0 Hz, 2H), 2.93-2.90 (m, 2H);MS (ES+) m/z 298.0 (M+1).

EXAMPLE 3.5 Synthesis of6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 249-251° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ10.74 (s, 1H), 7.18-7.13 (m, 1H), 6.79-6.42(m, 2H), 6.55 (s, 1H), 6.42 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz,2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 298.0 (M+1).

EXAMPLE 3.6 Synthesis of3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

To a stirred solution of1-(4-methoxybenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(3.00 g, 7.76 mmol) in dichloromethane (20 mL) and trifluoroacetic acid(20 mL) was added trifluoromethanesulfonic acid (6.8 mL, 76.8 mmol). Thereaction mixture was stirred at ambient temperature for 22 h, andconcentrated in vacuo. The residue was basified with saturated sodiumbicarbonate solution and extracted with ethyl acetate. The combinedorganic solution was washed with water and brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by column chromatography with ethyl acetate inhexanes (gradient 30% to 80%) to give3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(1.72 g, 76%): mp 226-227° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ10.82 (s, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.27 (m, 1H), 7.11-7.04(m, 2H), 6.97-6.90 (m, 2H), 4.89 (AB, 2H), 2.40 (s, 3H); MS (ES+) m/z292.9 (M+1).

EXAMPLE 3.7 Synthesis of5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one wasobtained (82%) as a colorless solid: mp 222-225° C.; ¹H NMR (300 MHz,CDCl₃) δ8.33 (s, 1H), 7.29-7.21 (m, 1H), 7.12 (d, J=6.7 Hz, 1H), 7.03(ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.59 (d, J=6.8Hz, 1H), 6.52 (d, J=10.1 Hz, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.68 (d, J=9.1Hz, 1H), 3.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ179.9, 157.2, 149.3,149.1 (d, J=12.4 Hz), 146.1, 140.2, 132.2, 129.1, 123.8 (d, J=42.8 Hz),118.6 (d, J=7.1 Hz), 110.7, 110.4, 96.3, 80.5, 58.6, 56.4; MS (ES+) m/z286.2 (M+1).

EXAMPLE 3.8 Synthesis of5-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (87%):mp 224-226° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 7.23 (ddd,J=7.7, 7.7, 0.9 Hz, 1H), 7.09 (d, J=7.0 Hz, 1H), 7.06-6.87 (m, 4H), 6.58(dd, J=8.0, 2.7 Hz, 1H), 4.80 (d, J=9.3 Hz, 1H), 4.67 (d, J=9.3 Hz, 1H);¹³C NMR (75 MHz, DMSO-d₆) δ178.2, 158.9, 157.1, 142.3, 132.4, 131.3,131.1, 129.5, 124.3, 122.8, 116.5, 116.2, 111.0, 110.9, 110.7, 110.4,80.2, 58.4; MS (ES+) m/z 260.0 (M+1).

EXAMPLE 3.9 Synthesis of6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (98%)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.23-8.11 (br, 1H),7.30-6.90 (m, 4H), 6.69 (d, J=8.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 6.39(dd, J=8.4, 1.8 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H),3.78 (s, 3H); MS (ES+) m/z 268.3 (M+1).

EXAMPLE 3.10 Synthesis of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (89%) as a colorless solid: mp>250° C. (diethyl ether); ¹HNMR (300 MHz, DMSO-d₆) δ10.57 (s, 1H), 7.24 (ddd, J=7.7, 7.7, 1.0 Hz,1H), 7.09 (d, J=6.9 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 6.49 (s, 1H), 6.16 (s, 1H), 4.73 (d, J=9.2 Hz, 1H), 4.60(d, J=9.2 Hz, 1H), 4.20-4.15 (m, 2H), 4.13-4.08 (m, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ178.3, 154.6, 144.0, 141.7, 137.7, 132.5, 128.7, 123.7,122.2, 121.4, 111.1, 109.8, 98.6, 79.4, 64.2, 63.6, 57.6; MS (ES+) m/z296.3 (M+1).

EXAMPLE 3.11 Synthesis of3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzo-dioxepine-9,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 235-236° C. (methanol); ¹HNMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 7.24 (dd, J=7.8, 7.2 Hz, 1H),7.11 (d, J=7.2 Hz, 1H), 6.97 (dd, J=7.8, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz,1H), 6.58 (s, 1H), 6.27 (s, 1H), 4.78 (d, J=9.3 Hz, 1H), 4.65 (d, J=9.3Hz, 1H), 4.14-4.01 (m, 2H), 3.98-3.87 (m, 2H), 2.06-1.97 (m, 2H); ¹³CNMR (75 MHz, DMSO-d₆) δ178.2, 156.3, 152.5, 145.8, 141.8, 132.4, 128.8,123.8, 123.7, 122.3, 115.6, 109.8, 103.0, 79.8, 70.7, 57.6, 31.9; MS(ES+) m/z 310.0 (M+1).

EXAMPLE 3.12 Synthesis of2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one wasobtained (62%) as a colorless solid: mp 242-244° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃) δ8.20 (br s, 1H), 7.36 (d, J=8.7 Hz, 1H), 7.30-7.24(m, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.99-6.93 (m,1H), 6.96 (d, J=7.8 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.0 Hz,1H), 2.41 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ176.2, 165.2, 151.4, 146.1,142.0, 138.2, 130.6, 130.1, 125.0, 123.1, 114.3, 111.5, 110.9, 88.4,76.3, 14.6; MS (ES+) m/z 331.1 (M+39).

EXAMPLE 3.13 Synthesis of3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dioneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dionewas obtained (88%) as a colorless solid: mp>250° C. (diethyl ether); ¹HNMR (300 MHz, DMSO-d₆) δ10.64 (br s, 1H), 7.30-7.22 (m, 1H), 7.09 (d,J=7.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.75 (s, 1H), 4.82 (d, J=9.3 Hz, 1H),4.70 (d, J=9.3 Hz, 1H), 3.30 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.2,157.0, 154.5, 141.8, 136.2, 132.8, 132.4, 128.9, 123.8, 122.3, 122.0,109.9, 104.9, 92.3, 79.8, 57.8, 28.2; MS (ES+) m/z 309.1 (M+1).

EXAMPLE 3.14 Synthesis of1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dioneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1-(diphenylmethyl)-1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dionewas obtained (53%) as a colorless solid: mp>250° C. (methanol); ¹H NMR(300 MHz, DMSO-d₆) δ10.69 (br s, 1H), 7.30-7.25 (m, 1H), 7.14-7.08 (m,2H), 7.01-6.92 (m, 2H), 6.69 (s, 1H), 4.82 (d, J=9.3 Hz, 1H), 4.70 (d,J=9.3 Hz, 1H), 3.20 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.2, 156.1,154.2, 142.5, 141.9, 132.4, 128.9, 126.0, 124.0, 122.4, 109.9, 104.0,93.9, 79.8, 57.8, 28.1; MS (ES+) m/z 308.9 (M+1).

EXAMPLE 3.15 Synthesis of7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (78%) as a colorless solid: mp>250° C. (diethyl ether); ¹HNMR (300 MHz, DMSO-d₆) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d,J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s 1H), 4.80 (d,J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); ¹³CNMR (75 MHz, DMSO-d₆) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4,122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS(ES+) m/z 313.7 (M+1), 315.7 (M+1).

EXAMPLE 3.16 Synthesis of7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using7-fluoro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (97%) as a colorless solid: mp>250° C. (diethyl ether); ¹HNMR (300 MHz, DMSO-d₆) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d,J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s 1H), 4.80 (d,J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); ¹³CNMR (75 MHz, DMSO-d₆) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4,122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS(ES+) m/z 298.0 (M+1).

EXAMPLE 3.17 Synthesis of4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (76%) as a colorless solid: mp>250° C. (diethylether); ¹HNMR (300 MHz, DMSO-d₆) δ10.84 (s, 1H), 7.12-7.07 (m, 1H), 6.72-6.65 (m,1H), 6.59 (s, 1H), 6.37 (s, 1H), 4.78-4.73 (m, 2H), 4.50 (t, J=8.7 Hz,2H), 2.97 (d, J=8.7 Hz, 2H), 2.20 (s, 3H); MS (ES+) m/z 311.9 (M+1).

EXAMPLE 3.18 Synthesis of6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′1-1)-one

A suspension of6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.60 g, 1.2 mmol) in methanol (20 mL) was degassed by bubbling throughnitrogen for 1 h before palladium hydroxide on carbon (20%, 0.08 g, 0.12mmol) was added. The mixture was stirred under 120 psi hydrogen at 60°C. for 16 h. The mixture was filtered through a pad of celite, and thefiltrate was concentrated in vacuo. The residue obtained wasrecrystallized from ethyl acetate and hexanes to afford6-hydroxy-2H-spiro[benzofuran-3,3′-indolin]-2′-one (0.25 g, 83%) as acolorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 10.86-9.35 (br, 2H), 7.19(td, J=7.6, 1.2 Hz, 1H), 7.03 (d, J=7.3 Hz, 1H), 6.96-6.84 (m, 2H), 6.42(d, J=8.2 Hz, 1H), 6.29 (d, J=2.1 Hz, 1H), 6.17 (dd, J=8.2, 2.1 Hz, 1H),4.72 (d, J=9.2 Hz, 1H), 4.59 (d, J=9.2 Hz, 1H); MS (ES+) m/z 254.1(M+1).

EXAMPLE 3.19 Synthesis of tert-butyl(3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate

To a solution of1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.45 g, 1.07 mol), tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate(0.60 g, 3.22 mmol) and triphenylphosphine (0.70 g, 2.68 mmol) intetrahydrofuran (50 mL) was added diethyl azodicarboxylate (0.42 mL,2.68 mmol) slowly at 0° C. The mixture was stirred to 16 h at ambienttemperature, then concentrated in vaccuo. The residue was purified bycolumn chromatography (ethyl acetate/hexanes-1:2) to afford tert-butyl(3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylateas an oil (0.52 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ7.43-7.25 (m, 10H),7.16-7.06 (m, 1H), 7.07-6.91 (m, 3H), 6.58-6.43 (m, 3H), 6.38-6.25 (m,1H), 5.00 (d, J=9.0 Hz, 1H), 4.80 (s, 1H), 4.73 (d, J=9.0 Hz, 1H),3.65-3.36 (m, 4H), 2.22-1.95 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 611.3(M+23).

EXAMPLE 3.20 Synthesis of tert-butyl(3S)-3-[(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate

A suspension of tert-butyl(3S)-3-{[1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl]oxy}pyrrolidine-1-carboxylate(0.50 g, 0.85 mmol) in methanol (20 mL) was degassed by bubbling throughnitrogen for one hour before palladium hydroxide on carbon (20%, 0.084g) was added. The mixture was stirred under 120 psi hydrogen at 60° C.for 48 h. The mixture was filtered through a pad of celite, the filtratewas concentrated in vacuo. The obtained residue was recrystallized fromethyl acetate and hexanes to afford tert-butyl(3S)-3-[(2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate(0.25 g, 70%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.01 (br s,1H), 7.29-7.09 (m, 1H), 7.12 (d, J=7.0 Hz, 1H), 7.02 (dd, J=7.5, 0.8 Hz,1H), 6.92 (d, J=7.7 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.47 (d, J=2.1 Hz,1H), 6.33 (dd, J=8.3, 2.1 Hz, 1H), 4.96 (d, J=9.1 Hz, 1H), 4.81 (s, 1H),4.69 (d, J=9.1 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s,9H); MS (ES+) m/z 445.0 (M+23).

EXAMPLE 3.21 Synthesis of6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one

A solution of1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one(0.61 g, 1.32 mmol) and triethylsilane (0.67 mL, 4.2 mmol) intrifluoroacetic acid (4.5 mL) was stirred at reflux under nitrogen for2.5 h. Once cooled, the reaction was diluted with water (40 mL) andextracted with ethyl acetate (3×25 mL). The combined organic solutionwas washed with brine (50 mL), dried (sodium sulfate), filtered andconcentrated under reduced pressure. The residue was dissolved into 10%diethyl ether in dichloromethane (5 mL) and, after standing at ambienttemperature, yielded a colorless precipitate. This material wascollected by filtration and washed with hexanes. Drying in air provided6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one (0.25g, 63%) as a colorless solid. An additional portion (0.14 g, 37%) ofproduct was also recovered by concentrating the filtrate and trituratingthe residual solid with hexanes: mp 216-220° C. (hexanes); ¹H NMR (300MHz, DMSO-d₆) δ10.58 (s, 1H), 7.23 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.08(d, J=7.2 Hz, 1H), 6.98-6.91 (m, 2H), 6.36 (s, 1H), 6.31 (s, 1H), 4.74(d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.05 (dd, J=5.1, 4.8 Hz, 2H),2.61-2.45 (m, 2H), 1.84-1.77 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.6,159.5, 155.4, 141.8, 132.9, 128.6, 123.8, 123.6, 122.3, 121.4, 114.8,109.7, 97.9, 79.5, 66.0, 57.3, 23.9, 21.7; MS (ES+) m/z 294.1 (M+1).

EXAMPLE 3.22 Synthesis of1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dioneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dionewas obtained (73%) as a colorless solid: mp>250° C. (ethyl acetate); ¹HNMR (300 MHz, DMSO-d₆) δ 10.62 (br s, 1H), 7.29-7.22 (m, 1H), 7.11 (d,J=7.1 Hz, 1H), 7.02-6.90 (m, 2H), 6.70 (s, 1H), 6.48 (s, 1H), 4.80 (d,J=9.2 Hz, 1H), 4.66 (d, J=9.2 Hz, 1H), 4.58 (s, 2H), 3.07 (s, 3H); ¹³CNMR (75 MHz, DMSO-d₆) δ178.1, 163.3, 156.7, 146.2, 141.9, 132.3, 128.9,124.0, 123.9, 122.9, 122.3, 109.9, 99.1, 80.3, 67.1, 57.7, 28.0; MS(ES+) m/z 322.9 (M+1).

EXAMPLE 3.23 Synthesis of4-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione

A solution of7-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one(3.4 g, 7.1 mmol) in anhydrous tetrahydrofuran (30 mL) was deoxygenatedfor 1 h with dry argon. Cesium carbonate (8.1 g, 25 mmol) andchloroiodomethane (1.5 mL, 21 mmol) were added and the heterogeneousreaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was filtered through a pad of diatomaceous earth andthe pad was washed with ethyl acetate (50 mL). The filtrate wasconcentrated in vacuo and the crude product was purified by columnchromatography with ethyl acetate in hexanes (10% to 70% gradient) toafford6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one.To a solution containing6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one(1.0 g, 20 mmol), in trifluoroacetic acid (10 mL) was addedtriethylsilane (1.6 mL, 10 mmol) and the reaction mixture was heated atreflux for 16 h. The reaction mixture was concentrated in vacuo and thecrude product was purified by column chromatography with ethyl acetatein hexanes (10% to 60% gradient) to afford4-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione(0.52 g, 78%) as an off-white solid: mp>250° C.; ¹F1 NMR (300 MHz,DMSO-d₆) δ10.63 (s, 1H), 7.28-7.23 (m, 1H), 7.10 (d, J=7.1 Hz, 1H),6.99-6.90 (m, 2H), 6.87 (s, 1H), 6.36 (s, 1H), 4.81 (d, J=9.3 Hz, 1H),4.70 (d, J=9.3 Hz, 1H), 4.51 (s, 2H), 3.26 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ178.0, 164.4, 156.0, 141.7, 139.2, 132.2, 130.7, 128.8, 123.7,123.0, 122.2, 110.8, 109.8, 97.8, 79.7, 67.0, 57.6, 28.1; MS (ES−) m/z321.2 (M−1).

EXAMPLE 3.24 Synthesis of2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-1′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one wasobtained (63%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 9.33 (s,1H), 7.32-6.90 (m, 4H), 6.38 (s, 1H), 6.34 (s, 1H), 4.80-4.71 (m, 1H),4.46 (t, J=8.6 Hz, 2H), 4.37-4.29 (m, 1H), 2.93 (t, J=8.5 Hz, 2H),2.30-2.13 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ182.7, 160.6, 155.5, 140.5,135.9, 128.3, 124.0, 123.8, 123.0, 120.3, 112.1, 110.1, 98.5, 71.9,62.0, 48.5, 32.4, 28.9; MS (ES+) m/z 293.8 (M+1)

EXAMPLE 3.25 Synthesis of(3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g,0.10 g per run) was resolved on a semi-prep chiral IA column with 10%acetonitrile in tert-butyl methylether.(3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one wasisolated as a crystalline colorless solid (0.96 g, 89% recovery): ee>99%(analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether);mp>250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.57 (s, 1H), 7.23 (ddd, J=7.6,7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s,1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s,1H), 1.95 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ179.2, 160.4, 158.9,142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3,80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.0 (M+1).

EXAMPLE 3.26 Synthesis of(3R)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g,0.10 g per run) was resolved on a semi-prep chiral IA column with 10%acetonitrile in tert-butyl methylether.(R)-6-methoxy-5-methyl-2H-spiro[benzofuran-3,3′-indolin]-2′-one wasisolated as a crystalline colorless solid (0.81 g, 75% recovery): ee>99%(analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether);mp>250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.57 (s, 1H), 7.23 (ddd, J=7.6,7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s,1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s,1H), 1.95 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ179.2, 160.4, 158.9,142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3,80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.1 (M+1).

EXAMPLE 3.27 Synthesis of7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.59 g, 1.2 mmol) in trifluoroacetic acid (25 mL) was addedtriethylsilane (0.6 mL, 3.7 mmol). The reaction mixture was heated atreflux for 1 h, allowed to cool to ambient temperature and concentratedin vacuo. The residue was purified by column chromatography and elutedwith a gradient of ethyl acetate in hexanes, followed by sequentialtrituration in acetonitrile and ethyl acetate, to afford7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.101 g, 26%) as an off-white solid: MS (ES+) m/z 314.2 (M+1).

EXAMPLE 3.28 Synthesis of 2′,3′,5,6-tetrahydrospiro[benzo[1,2-1):5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one

To a solution of6′-(diphenylmethyl)-2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one(0.5 g, 1.0 mmol) in trifluoroacetic acid (7 mL) was addedtriethylsilane (0.47 mL, 3.0 mmol). The reaction mixture was heated atreflux for 3.5 h and concentrated in vacuo. The residue was trituratedin methanol to afford2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′-[1,4]dioxino[2,3-f]indol]-7′(6′H)-one(0.076 g, 23%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.30 (s, 1H), 6.61 (s, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 6.36(s, 1H), 4.66 (ABq, J=36.8, 9.2 Hz, 2H), 4.54-4.44 (m, 2H), 4.24-4.11(m, 4H), 3.02-2.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.8, 160.8,160.4, 143.3, 138.7, 135.4, 125.1, 120.9, 119.5, 118.9, 113.0, 99.0,92.2, 79.7, 72.0, 64.2, 63.7, 57.1, 28.3; MS (ES+) m/z 337.9 (M+1).

EXAMPLE 3.29 Synthesis of6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

To a stirred solution of6-methoxy-1-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.50 g, 1.2 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5mL) was added trifluoromethanesulfonic acid (1.0 mL, 11 mmol). Thereaction mixture was stirred at ambient temperature for 18 h andconcentrated in vacuo. The residue was basified with saturated aqueoussodium bicarbonate and extracted with ethyl acetate. The organic phasewas washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by column chromatography to afford6-methoxy-2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.34 g, 96%): mp 185-186° C.; ¹H NMR (300 MHz, CDCl₃) δ8.46 (s, 1H),7.30-7.25 (m, 1H), 7.11-7.03 (m, 2H), 6.97-6.94 (m, 2H), 6.56 (s, 1H),4.91 (ABq, 2H), 3.90 (s, 3H); MS (ES+) m/z 292.9 (M+1).

EXAMPLE 3.30 Synthesis of6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 3.29 and makingnon-critical variations using6-fluoro-1-(4-methoxybenzyl)-2′-oxo-1,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace of6-methoxy-1-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile,6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (85%): mp 222-224° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 10.70(s, 1H), 7.40-7.38 (m, 1H), 7.28-7.23 (m, 2H), 7.17-7.15 (m, 1H),6.99-6.90 (m, 2H), 4.91 (ABq, 2H); MS (ES+) m/z 280.9 (M+1).

EXAMPLE 3.31 Synthesis of6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione

A suspension of methyl6-methyl-8-(2-nitrophenyl)-7-oxo-2,3,7,8-tetrahydro-6H-[1,4]dioxino[2,3-f]indole-8-carboxylate(0.21 g, 0.54 mmol) and 10% w/w palladium on carbon (0.1 g) in methanol(20 mL) was hydrogenated at 1 atm and at ambient temperature for 20 h.The mixture was filtered through a pad of diatomaceous earth and thefiltrate was concentrated in vacuo. The residue was subjected to columnchromatography to afford6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione(0.07 g, 40%): MS (ES+) m/z 323.0 (M+1).

EXAMPLE 3.32 Synthesis of4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1W)-one(5.38 g, 9.96 mmol), triethylsilane (7.93 mL, 49.8 mmol) andtrifluoroacetic acid (25.9 mL, 348 mmol) was heated at 75° C. for 8 h.The reaction mixture was allowed to cool to ambient temperature,concentrated in vacuo. The residue was triturated in diethyl ether,purified by column chromatography and eluted with a 0% to 25% gradientof ethyl acetate in dichloromethane to afford4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.79 g, 48%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.89 (s, 1H), 7.27 (dd, J=7.9, 7.9 Hz, 1H), 7.14 (d, J=7.8Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.53 (s, 1H), 5.98 (s, 1H), 5.63 (ABq,2H), 4.20-4.12 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 148.7, 145.1,144.3, 139.1, 133.0, 128.7, 126.8, 120.0, 112.6, 112.2, 110.2, 105.4,87.7, 77.6, 64.7, 64.3; MS (ES+) m/z 359.6 (M+1), 361.6 (M+1).

EXAMPLE 3.33 Synthesis of4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A solution of1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.18 g, 2.45 mmol) and triethylsilane (1.21 g, 9.84 mmol) intrifluoroacetic acid (20 mL) was heated at 65° C. for 16 h. Aftercooling to ambient temperature, the reaction mixture was concentrated invacuo. The residue was recrystallized from N,N′-dimethylformamide/waterto afford4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.65 g, 84%) as a colourless solid: mp 282-285° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.83 (s, 1H), 7.30 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.78 (d,J=8.0 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 6.47 (s, 1H), 6.27 (s, 1H), 4.71(dd, J=9.4 Hz, 2H), 4.14 (dd, J=5.3, 3.2 Hz, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.3, 160.9 (d, ¹J_(C-F)=244 Hz), 147.0, 143.3 (d,²J_(C-F)=96.3 Hz), 135.5, 131.9, 131.2 (d, ⁴J_(C-F)=2.9 Hz), 128.6,128.5, 123.2 (d, ²J_(C-F)=120 Hz), 116.4 (d, ³J_(C-F)=22.8 Hz), 115.1,108.2, 103.3, 74.3, 64.2, 63.7; MS (ES+) m/z 313.1 (M+1).

EXAMPLE 3.34 Synthesis of4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (99%) as a light yellow solid: mp 221-224° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 10.79 (s, 1H), 8.41 (d,J=2.2 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.75-7.68 (m, 1H), 7.58-7.53 (m,2H), 7.40-7.33 (m, 2H), 7.04-7.00 (m, 1H), 6.93-6.88 (m, 1H), 6.36 (s,1H), 5.84 (s, 1H), 4.42 (d, J=9.5 Hz, 1H), 4.25 (d, J=9.5 Hz, 1H),4.25-4.05 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 179.0, 155.1, 150.5,146.9, 144.6, 142.6, 138.3, 136.4, 135.5, 131.8, 130.1, 129.5, 129.1,128.6, 127.3, 127.0, 124.8, 123.0, 111.2, 110.4, 98.9, 78.27, 64.7,64.2, 58.4; MS (ES+) m/z 422.8 (M+1).

EXAMPLE 3.35 Synthesis of4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (74%) as an off-white solid: mp 243-246° C. (diethylether); ¹H NMR (300 MHz, CDCl₃) δ 8.63-8.53 (m, 2H), 8.07 (d, J=8.5 Hz,1H), 7.74-7.64 (m, 2H), 7.57-7.39 (m, 2H), 7.36-7.19 (m, 3H), 7.02-6.93(m, 2H), 6.50 (s, 1H), 5.96 (s, 1H), 5.28 (d, J=15.8 Hz, 1H), 4.98 (d,J=15.8 Hz, 1H), 4.69 (d, J=9.2 Hz, 1H), 4.34 (d, J=9.2 Hz, 1H),4.32-4.08 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 155.4, 150.3, 149.6,147.2, 144.8, 142.7, 138.2, 137.2, 136.3, 135.7, 131.2, 130.4, 129.7,129.2, 128.0, 126.9, 128.0, 126.9, 125.6, 122.9, 122.7, 121.8, 111.3,109.5, 99.6, 64.6, 64.1, 58.4, 46.3; MS (ES+) m/z 463.9 (M+1).

EXAMPLE 3.36 Synthesis of2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile

To a suspension of1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile(1.9 g, 4.4 mmol) in triethylsilane (5.0 mL) was added trifluoroaceticacid (10.0 mL). The solution was heated at reflux for 6 h, allowed tocool to ambient temperature and concentrated in vacuo to obtain2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile (0.86g, 74%) as a colorless solid which was carried forward withoutpurification MS (ES+) m/z 263.0 (M+1).

EXAMPLE 3.37 Synthesis of5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of1-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.33 g, 0.70 mmol) in triethylsilane (2 mL) was added trifluoroaceticacid (5 mL). The reaction mixture was heated at 65° C. for 16 h, allowedto cool to ambient temperature and concentrated in vacuo to afford5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.21 g, 60%): MS (ES+) m/z 309.9 (M+1).

EXAMPLE 3.38 Synthesis of9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: MS (ES+) m/z 313.8 (M+1).

Example 3.39 Synthesis of7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one wasobtained (68%) as an off-white solid: MS (ES+) m/z 293.8 (M+1).

EXAMPLE 3.40 Synthesis ofspiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one 5,5′-dioxide

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one5,5′-dioxide to replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one 5,5′-dioxidewas obtained (43%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ11.01-10.88 (m, 1H), 7.86-7.67 (m, 1H), 7.40-6.96 (m, 6H), 6.40-6.30 (m,1H), 5.07-4.80 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7, 165.5, 141.8,135.1, 131.6, 130.1, 128.9, 128.1, 127.2, 126.5, 124.8, 124.0, 123.3,111.3, 110.9, 80.9, 56.7; MS (ES+) m/z 325.8 (M+1).

EXAMPLE 3.41 Synthesis ofspiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one wasobtained (88%) as a colorless solid: mp>220° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 11.69 (s, 1H), 8.96-8.89 (m, 1H), 8.47-8.40 (m, 1H),8.16-7.70 (m, 4H), 5.93 (d, J=9.3 Hz, 1H), 5.82 (d, J=9.3 Hz, 1H); MS(ES+) m/z 280.0 (M+1).

EXAMPLE 3.42 Synthesis of6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using6-chloro-t-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-onewas obtained (81%) as a colorless solid: mp 255-257° C.; ¹H NMR (300MHz, DMSO-d₆) δ10.66 (s, 1H), 7.23 (dd, J=7.5, 1.2 Hz, 1H), 7.11 (d,J=7.5 Hz, 1H), 6.96 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.85 (m, 2H), 4.72(ABq, 2H), 4.14-3.92 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.7, 151.0,141.6, 138.9, 138.1, 131.0, 128.7, 123.5, 122.2, 117.3, 117.1, 109.6,104.8, 81.1, 64.4, 63.6, 57.3; MS (ES+) m/z 330.1 (M+1), 332.1 (M+1).

EXAMPLE 3.43 Synthesis of2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

6-chloro-1-(diphenylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one(2.1 g, 4.24 mmol) was suspended in methanol (20 mL) and ethyl acetate(80 mL) in a steel bomb and palladium on carbon (20% w/w, 0.45 g) wasadded. The bomb was pressurized with hydrogen gas (120 psi) and themixture was stirred at 60° C. for 16 h. The reaction mixture was allowedto cool to ambient temperature and filtered through a pad ofdiatomaceous earth. The filtrate was concentrated in vacuo and theresidue triturated with ethyl acetate to afford2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one(0.522 g, 42%) as a colorless solid: mp 259-261° C.; ¹H NMR (300 MHz,CD₃OD) δ7.27-7.18 (m, 1H), 7.09-6.88 (m, 3H), 6.70 (d, J=8.7 Hz, 1H),6.39 (d, J=8.7 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.59 (d, J=9.0 Hz, 1H),4.12-3.90 (m, 4H); ¹³C NMR (75 MHz, CD₃OD) δ181.0, 157.5, 142.4, 141.3,139.6, 133.9, 129.8, 124.5, 124.0, 119.0, 117.1, 111.0, 102.9, 82.4,66.0, 65.2, 59.1; MS (ES+) m/z 296.2 (M+1).

EXAMPLE 3.44 Synthesis of5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of1-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′1-1)-one(6.06 g, 13.8 mmol) in methanol (100 mL), ethyl acetate (25 mL) andacetic acid (1 mL) in a steel bomb was added palladium on carbon (20%w/w, 2.0 g). The bomb was pressurized with hydrogen (50 psi) and thereaction mixture was heated at 65° C. for 16 h. The reaction mixtureallowed to cool to ambient temperature and was filtered through a pad ofdiatomaceous earth. The pad was washed with ethyl acetate (15 mL) andmethanol (50 mL). The filtrate was concentrated in vacuo and the residuewas triturated in methanol to afford5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.63 g, 96%) asa colorless solid. mp>200° C.; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (s, 1H),7.32-7.27 (m, 1H), 7.15-7.05 (m, 2H), 6.97 (d, J=7.8 Hz, 1H), 6.79 (dd,J=10.3, 6.3 Hz, 1H), 6.62 (dd, J=9.0, 8.0 Hz, 1H), 5.00 (d, J=9.2 Hz,1H), 4.73 (d, J=9.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ179.7, 156.70 (d,J_(C-F)=10.9 Hz), 151.3 (dd, J_(C-F)=248.7, 14.3 Hz), 145.7 (dd,J_(C-F)=241.6, 13.8 Hz), 140.3, 131.6, 129.4, 124.0, 123.7, 123.4 (dd,J_(C-F)=6.3, 3.1 Hz), 111.9 (d, J_(C-F)=20.4 Hz), 110.7, 100.1 (d,J_(C-F)=22.4 Hz), 80.7, 58.4; MS (ES+) m/z 274.2 (M+1).

EXAMPLE 3.45 Synthesis of5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-onewas obtained (80%) as a colorless solid: mp>230° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.13 (s, 1H), 7.33-7.19 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.04(dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.68 (s, 1H), 6.49 (s,1H), 4.92 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 2.76-2.72 (m, 2H),2.58-2.56 (m, 2H), 1.71 (t, J=3.2 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃)δ180.5, 158.7, 140.4, 139.0, 132.9, 130.2, 128.8, 126.0, 124.1, 123.6,123.3, 110.3, 110.2, 79.6, 58.6, 30.0, 29.0, 23.2, 23.0; MS (ES+) m/z292.0 (M+1).

EXAMPLE 3.46 Synthesis of6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one wasobtained (69%): mp 172-174° C.; ¹H NMR (300 MHz, CDCl₃) δ8.56 (s, 1H),7.23-7.18 (m, 1H), 7.15-7.06 (m, 1H), 7.06-6.97 (m, 1H), 6.97-6.89 (m,1H), 6.89-6.82 (m, 1H), 6.82-6.74 (m, 1H), 6.38 (s, 1H), 4.80 (ABq, 2H),4.03-3.80 (m, 2H), 3.67-3.54 (m, 2H), 3.35 (s, 3H); MS (ES+) m/z 312.0(M+1).

EXAMPLE 3.47 Synthesis of5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one wasobtained (30%): ¹H NMR (300 MHz, CDCl₃) δ8.38 (s, 1H), 7.24-7.18 (m,1H), 7.15-7.07 (m, 1H), 7.06-6.97 (m, 1H), 6.96-6.88 (m, 1H), 6.70-6.61(m, 1H), 6.54 (s, 1H), 6.43-6.35 (m, 1H), 4.82 (ABq, 2H), 4.13-3.98 (m,2H), 3.75-3.67 (m, 2H), 3.42 (s, 1H).

EXAMPLE 3.48 Synthesis of2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-onewas obtained (30%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.56 (s, 1H), 7.23 (ddd, J=7.7, 7.7, 0.5 Hz, 1H), 7.13 (d,J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.21 (ABq, 2H), 4.76 (ABq, 2H), 4.26(s, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.3, 148.7, 144.5, 141.8, 132.3,129.2, 128.6, 123.8, 122.5, 122.2, 114.1, 109.7, 80.2, 64.1, 63.9, 57.7;MS (ES+) m/z 295.9 (M+1).

EXAMPLE 3.49 Synthesis of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one

To a solution of6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one(1.9 g, 4.0 mmol) in dichloromethane (40 mL) and trifluoroacetic acid(40 mL) was added at ambient temperature trifluoromethanesulfonic acid(1.8 mL, 20 mmol). The mixture was stirred at ambient temperature for 16h and concentrated in vacuo. Water was added to the residue and themixture was extracted with ethyl acetate. The combined organic extractswere washed with saturated aqueous sodium bicarbonate and water, driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography and eluted with 50%ethyl acetate in hexanes to afford2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one(0.65 g, 44%): ¹H NMR (300 MHz, CDCl₃) δ10.86 (s, 1H), 9.06 (s, 1H),7.97 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 6.21 (s,1H), 4.68 (s, 2H), 4.19-4.01 (m, 4H); MS (ES+) m/z 353.1 (M+1).

EXAMPLE 3.50 Synthesis of4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%): ¹H NMR (300 MHz, CDCl₃) δ10.42 (s, 1H), 6.35 (s,1H), 6.15 (d, J=2.0 Hz, 1H), 6.10 (d, J=2.0 Hz, 1H), 6.08 (s, 1H), 4.58(ABq, 2H), 4.17-4.03 (m, 4H), 3.72 (s, 3H), 3.58 (s, 3H); MS (ES+) m/z356.1 (M+1).

EXAMPLE 3.51 Synthesis ofspiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 3 and makingnon-critical variations using1′-(diphenylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-oneto replace1-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one was obtained (22%):mp 206-207° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ10.78 (s, 1H), 8.68-8.61 (m, 2H), 8.06 (d, J=9.0 Hz, 1H), 7.68 (d, J=9.0Hz, 1H), 7.21-7.18 (m, 1H), 7.03-6.86 (m, 3H), 6.96 (ABq, 2H); MS (ES+)m/z 289.8 (M+1).

EXAMPLE 4 Synthesis of1′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.28 g, 1.0 mmol), 2-(bromomethyl)tetrahydro-2H-pyran (0.36 g, 2.0mmol) and cesium carbonate (1.00 g, 3.0 mmol) was stirred in butanone at80° C. for 3 h. Upon cooling to ambient temperature, the reactionmixture was filtered, and the filtrate was evaporated under reducedpressure. The residue was subjected to column chromatography with ethylacetate-hexanes (1:5-1:1) to afford1′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.31 g, 82%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.38-6.94(m, 4H), 6.47 (d, J=2.9 Hz, 1H), 6.38 (s, 1H), 4.79 (ABq, 2H), 4.50 (t,J=8.6 Hz, 2H), 4.01-3.61 (m, 4H), 3.37 (t, J=11.1 Hz, 1H), 2.97 (t,J=8.4 Hz, 2H), 1.97-1.27 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ178.1 (2C),161.7 (2C), 161.3, 161.2, 143.2, 143.1, 132.8, 132.7, 128.6 (2C), 123.5,123.1, 123.1, 120.6, 120.5, 119.8 (2C), 119.0, 118.9, 109.7, 93.2, 93.1,80.6, 75.7, 75.5, 72.3, 68.4 (2C), 57.7, 57.6, 45.8, 45.7, 29.6, 29.5,29.1, 25.8, 23.0; MS (ES+) m/z 378.3 (M+1).

EXAMPLE 4.1 Synthesis of1′-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(1.05 g, 3.73 mmol), 4-bromobenzyl bromide (1.21 g, 4.84 mmol) andcesium carbonate (1.84 g, 5.65 mmol) in 2-butanone (25 mL) was stirredat ambient temperature for 16 h. The mixture was diluted with ethylacetate and filtered through Celite. The filtrate was concentrated todryness under reduced pressure. The residue was purified by flash columnchromatography with hexanes/ethyl acetate (9:1, increased to 1:1) toafford1-(4-bromobenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(1.42 g, 84%) as a colorless solid: mp 148-150° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) δ7.48 (d, J=8.4 Hz, 2H), 7.25-7.17 (m, 4H), 7.05 (dd,J=7.5, 7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.12 (s, 1H),5.89 (s, 1H), 5.88 (s, 1H), 5.02 (d, J=15.6 Hz, 1H), 4.97 (d, J=9.0 Hz,1H), 4.78 (d, J=15.6 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H); ¹³C NMR (75 MHz,CDCl₃) δ177.8, 156.1, 149.1, 142.5, 141.9, 134.9, 132.3, 132.2, 129.3,129.1, 124.2, 123.8, 122.0, 119.4, 109.3, 103.1, 101.7, 93.8, 80.6,58.4, 43.7; MS (ES+) m/z 452.0 (M+1), 450.0 (M+1).

EXAMPLE 4.2 Synthesis of1′-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2-chloro-5-(chloromethyl)-1-methyl-1H-imidazole to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (42%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.42-7.01 (m, 4H), 6.94 (s, 1H), 6.42 (s, 1H), 6.40 (s, 1H), 5.03 (ABq,2H), 4.77 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.59 (s, 3H), 2.97 (t,J=8.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 162.0, 161.4, 141.7,141.7, 132.0, 129.1, 124.2, 124.0, 123.8, 120.1, 119.8, 119.6, 118.8,110.5, 93.3, 80.6, 72.4, 57.7, 37.8, 31.0, 29.0; MS (ES+) m/z 408.0(M+1), 410.0 (M+1).

EXAMPLE 4.3 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using (R)-(tetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (30%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.31-6.98 (m, 4H), 6.48 (s, 1H), 6.39 (s, 1H), 4.78 (ABq, 2H), 4.52 (t,J=8.6 Hz, 2H), 4.32-4.22 (m, 1H), 3.91-3.69 (m, 4H), 2.97 (t, J=8.4 Hz,2H), 2.09-1.64 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ178.3, 161.7, 161.3,142.8, 132.8, 128.7, 123.6, 123.2, 120.5, 119.8, 118.9, 109.6, 93.2,80.7, 76.8, 72.4, 68.2, 57.7, 44.6, 29.1, 29.0, 25.7; MS (ES+) m/z 364.1(M+1).

EXAMPLE 4.4 Synthesis of1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 1-bromo-3-methylbutane to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (58%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.36-6.84 (m, 4H), 6.44 (s, 1H), 6.39 (s, 1H), 4.77 (ABq, 2H), 4.51 (t,J=8.6 Hz, 2H), 3.88-3.64 (m, 2H), 3.04-2.90 (m, 2H), 1.75-1.54 (m, 3H),0.99 (d, J=6.2 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 161.7, 161.3,142.4, 133.1, 128.7, 123.9, 123.1, 120.4, 119.8, 118.8, 108.5, 93.2,80.6, 72.4, 57.7, 38.8, 36.2, 29.1, 26.1, 22.6, 22.5; MS (ES+) m/z 350.1(M+1).

EXAMPLE 4.5 Synthesis of1-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using (S)-(tetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (56%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.34-6.96 (m, 4H), 6.48 (d, J=1.51 Hz, 1H), 6.38 (s, 1H), 4.77 (ABq,2H), 4.50 (t, J=8.6 Hz, 2H), 4.32-4.21 (m, 1H), 3.98-3.64 (m, 4H), 2.96(t, J=8.7 Hz, 2H), 2.09-1.63 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 178.3,178.2, 161.7, 161.3, 142.9, 142.9, 142.8, 132.8, 132.7, 128.7, 128.7,123.7, 123.6, 123.2, 119.0, 118.9, 109.6, 109.5, 93.1, 80.7, 80.7, 76.9,76.8, 72.4, 68.3, 68.2, 57.7, 57.7, 44.7, 44.6, 29.3, 29.1 (2C), 25.7,25.6; MS (ES+) m/z 364.3 (M+1).

EXAMPLE 4.6 Synthesis of1′-(tetrahydro-2H-pyran-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(bromomethyl)tetrahydro-2H-pyran toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1-(tetrahydro-2H-pyran-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (69%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.37-6.85 (m, 4H), 6.43 (s, 1H), 6.39 (s, 1H), 4.76 (ABq, 2H), 4.51 (t,J=8.6 Hz, 2H), 3.97 (ABq, 2H), 3.77-3.52 (m, 2H), 3.40-3.28 (m, 2H),3.03-2.91 (m, 2H), 2.19-2.02 (m, 1H), 1.65-1.38 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ178.1, 161.8, 161.4, 142.8, 132.8, 128.8, 124.1, 123.3,120.2, 119.9, 118.8, 108.6, 93.3, 80.8, 72.4, 67.5, 57.7, 46.1, 33.9,30.8, 29.1; MS (ES+) m/z 378.3 (M+1).

EXAMPLE 4.7 Synthesis of methyl5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using methyl 5-(chloromethyl)furan-2-carboxylateto replace 2-(bromomethyl)tetrahydro-2H-pyran, methyl5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylatewas obtained (70%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)

7.28-6.23 (m, 5H), 6.49 (s, 1H), 6.39 (s, 1H), 6.37 (d, J=3.49 Hz, 1H),4.99 (ABq, 2H), 4.80 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.85 (s, 3H),3.05-2.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 161.9, 161.3, 158.8,153.5, 144.2, 141.4, 132.6, 128.9, 124.0, 123.8, 120.1, 120.0, 119.0,110.2, 109.0, 93.2, 80.5, 72.4, 57.7, 52.0, 37.4, 29.1; MS (ES+) m/z418.1 (M+1).

EXAMPLE 4.8 Synthesis of1′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(iodomethyl)-1,4-dioxane to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (48%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.39-6.96 (m, 4H), 6.45 (d, J=8.1 Hz, 1H), 6.38 (s, 1H), 4.89 (ABq, 2H),4.65 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.99-3.33 (m, 9H), 3.05-2.85 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ178.2, 178.1, 161.8, 161.8, 161.3, 161.2,142.6, 132.7, 132.6, 128.8, 128.7, 123.8, 123.7, 123.4, 120.3, 120.2,120.0, 119.9, 118.9, 118.8, 109.5, 109.3, 93.2, 80.6, 80.5, 73.2, 72.4,69.3, 69.2, 66.7, 66.6, 66.4, 57.6, 41.7 (2C), 29.1; MS (ES+) m/z 380.1(M+1).

EXAMPLE 4.9 Synthesis of1′-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using4-(chloromethyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (32%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.39(s, 1H), 7.29-6.84 (m, 4H), 6.42 (s, 1H), 6.38 (s, 1H), 4.89 (s, 2H),4.79 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.86 (s, 3H), 2.97 (t, J=8.6 Hz,2H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 161.9, 161.4, 141.6, 139.9, 139.4,138.9, 138.4, 132.5, 131.9, 128.9, 124.1, 123.7, 123.4, 120.0, 119.9,119.8, 118.8, 115.4, 108.8, 93.3, 80.6, 72.4, 57.6, 39.7, 34.0, 29.0; MS(ES+) m/z 442.0 (M+1).

EXAMPLE 4.10 Synthesis of1′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-(bromomethyl)tetrahydro-2H-pyran toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (45%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.42-6.83 (m, 4H), 6.44 (d, J=2.3 Hz, 1H), 6.39 (s, 1H), 4.88 (dd,J=8.9, 1.9 Hz, 1H), 4.63 (d, J=8.9 Hz, 1H), 4.51 (t, J=8.6 Hz, 2H),3.89-3.24 (m, 6H), 3.08-2.86 (m, 2H), 2.26-2.09 (m, 1H), 1.91-1.29 (m,5H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 178.0, 161.8, 161.4, 161.3, 142.5,142.4, 132.8, 132.8, 128.8, 124.0 (2C), 123.4, 120.2, 120.1, 120.0,119.9, 118.8 (2C), 108.6, 93.2, 93.2, 80.8, 72.4 (2C), 71.2, 71.0, 68.5,68.4, 57.7 (2C), 42.5, 42.4, 34.8, 29.1, 27.5, 27.4, 25.1, 24.8; MS(ES+) m/z 378.1 (M+1).

EXAMPLE 4.11 Synthesis of methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using methyl2-(bromomethyl)oxazole-4-carboxylate to replace2-(bromomethyl)tetrahydro-2H-pyran, methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylatewas obtained (61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.17(s, 1H), 7.27-6.91 (m, 4H), 6.53 (s, 1H), 6.38 (s, 1H), 5.12 (ABq, 2H),4.81 (ABq 2H), 4.51 (t, J=8.7 Hz, 2H), 3.89 (s, 3H), 3.04-2.91 (m, 2H);¹³C NMR (75 MHz, CDCl₃) δ177.6, 161.9, 161.2 (2C), 159.2, 145.0, 141.0,133.6, 132.5, 129.0, 124.1, 120.1, 119.9, 199.1, 108.8, 93.2, 80.5,72.4, 57.7, 52.3, 37.2, 29.0.

EXAMPLE 4.12 Synthesis of1′-(2-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 1-(bromomethyl)-2-fluorobenzene to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(2-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (81%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.41-6.81 (m, 8H), 6.47 (s, 1H), 6.41 (s, 1H), 5.02 (ABq, 2H), 4.83(ABq, 2H), 4.52 (t, J=8.7 Hz, 2H), 3.08-2.89 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ178.0, 162.3, 161.9, 161.4, 159.0, 141.9, 132.7, 129.7, 129.7(2C), 129.6, 128.9, 124.7, 124.6, 123.9, 123.5, 122.9, 122.7, 120.2,120.0, 119.0, 115.8, 115.5, 109.1, 109.0, 93.3, 80.7, 72.4, 57.8, 37.6,37.5, 29.1; MS (ES+) m/z 387.9 (M+1).

EXAMPLE 4.13 Synthesis of1′(4-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 1-(bromomethyl)-4-fluorobenzene to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(4-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.41-6.94 (m, 7H), 6.79 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.41 (s, 1H),4.91 (ABq, 2H), 4.83 (Abq, 2H), 4.53 (t, J=8.7 Hz, 2H), 3.08-2.89 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0, 164.0, 161.9, 161.4, 160.7, 141.9,132.8, 131.7, 131.6, 129.3, 129.2, 128.7, 124.0, 123.5, 120.2, 120.0,118.8, 116.0, 115.7, 109.1, 93.3, 80.6, 72.4, 57.7, 43.5, 29.1; MS (ES+)m/z 387.9 (M+1).

EXAMPLE 4.14 Synthesis of1′-benzyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using benzyl bromide to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-benzyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (89%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.43-6.96 (m, 8H), 6.80 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.42 (s, 1H),4.96 (ABq, 2H), 4.84 (ABq, 2H), 4.53 (t, J=8.7 Hz, 2H), 3.05-2.92 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 161.8, 161.4, 142.2, 135.8, 132.8,128.9, 128.7, 127.8, 127.4, 123.9, 123.4, 120.3, 120.0, 118.9, 109.3,93.3, 80.7, 72.4, 57.8, 44.2, 29.1; MS (ES+) m/z 369.9 (M+1).

EXAMPLE 4.15 Synthesis of1′-(biphenyl-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)biphenyl to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(biphenyl-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (39%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.67-6.81 (m, 13H), 6.50 (s, 1H), 6.44 (s, 1H), 5.00 (ABq, 2H), 4.86(ABq, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.09-2.90 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 178.0, 161.9, 161.4, 142.1, 140.8, 140.5, 134.8, 132.8, 128.8,127.9, 127.6, 127.5, 127.1, 123.9, 123.5, 120.3, 120.0, 118.9, 109.3,93.3, 80.7, 72.4, 57.8, 43.9, 29.1; MS (ES+) m/z 445.9 (M+1).

EXAMPLE 4.16 Synthesis of1′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-(bromomethyl)tetrahydrofuran to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.39-6.89 (m, 4H), 6.42 (s, 1H), 6.39 (s, 1H), 4.77 (ABq, 2H), 4.51 (t,J=8.6 Hz, 2H), 4.01-3.54 (m, 6H), 3.04-2.91 (m, 2H), 2.89-2.75 (m, 1H),2.10-1.95 (m, 1H), 1.82-1.68 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ178.1,178.0, 161.8, 161.3, 142.4 (2C), 132.8 (2C), 128.8, 124.0 (2C), 123.4,120.2, 120.1, 119.9 (2C), 118.7, 118.6, 108.4, 108.3, 93.2 (2C), 80.6,72.3, 71.1, 70.9, 67.6, 67.5, 57.6, 42.8, 42.7, 38.0 (2C), 29.8 (2C),29.1; MS (ES+) m/z 364.0 (M+1).

EXAMPLE 4.17 Synthesis of1-[(3-bromoisoxazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-bromo-5-(bromomethyl)isoxazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1-[(3-bromoisoxazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (58%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.36-6.88 (m, 4H), 6.44 (s, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 5.05 (ABq,2H), 4.80 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.07-2.89 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ178.1, 161.7, 161.2, 142.8, 132.6, 128.6, 123.6, 123.2,120.3, 119.8, 118.8, 109.4, 93.1, 80.6, 76.9, 72.3, 68.2, 57.6, 44.6,29.2, 29.0, 25.5; MS (ES+) m/z 438.7 (M+1), 440 (M+1).

EXAMPLE 4.18 Synthesis of1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-bromo-5-(bromomethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (94%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.33-6.96 (m, 4H), 6.46 (s, 1H), 6.40 (s, 1H), 6.28 (dd, J=23.3, 3.3Hz, 2H), 4.89 (ABq, 2H), 4.80 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H),3.07-2.88 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 161.8, 161.2, 151.0,141.5, 132.7, 128.7, 123.8, 123.6, 121.6, 120.1, 119.9, 118.9, 112.3,111.4, 109.0, 93.2, 80.4, 72.4, 57.6, 37.0, 29.0; MS (ES+) m/z: 437.7(M+1), 439.7 (M+1).

EXAMPLE 4.19 Synthesis of1′-(tetrahydrofuran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)tetrahydrofuran to replace2-(bromomethyl)tetrahydro-2H-pyran,t-(tetrahydrofuran-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (64%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.37-6.95 (m, 4H), 6.48 (d, J=1.2 Hz, 1H), 6.38 (s, 1H), 4.78 (ABq,2H), 4.50 (t, J=8.7 Hz, 2H), 4.31-4.21 (m, 1H), 3.98-3.65 (m, 4H), 2.96(t, J=8.7 Hz, 2H), 2.09-1.64 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ178.3,178.2, 161.7, 161.2, 142.8 (2C), 132.7, 132.6, 128.7, 123.6, 123.2,120.4 (2C), 119.8, 118.9 (2C), 109.5, 109.4, 93.1, 80.7, 80.6, 76.9,76.8, 72.3, 68.2, 68.1, 57.6 (2C), 44.6, 44.5, 29.2, 29.0, 25.6, 25.5;MS (ES+) m/z 363.8 (M+1).

EXAMPLE 4.20 Synthesis of1-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using oxetan-2-ylmethyl 4-methylbenzenesulfonateto replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (28%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.34-6.95 (m, 4H), 6.41 (d, J=9.2 Hz, 1H), 6.38 (s, 1H), 5.04-4.90 (m,1H), 4.80-4.62 (m, 2H), 4.52-4.30 (m, 4H), 4.08-3.76 (m, 2H), 2.91 (t,J=8.6 Hz, 2H), 2.70-2.56 (m, 1H), 2.44-2.33 (m, 1H); ¹³C NMR (75 MHz,CDCl₃) δ178.0, 177.8, 161.5, 161.0 (2C), 143.5, 143.4, 132.5, 132.4,129.0, 128.9, 123.8, 123.7, 123.3, 121.0 (2C), 120.3, 119.3, 119.2,110.3, 110.2, 92.9 (2C), 80.3 (2C), 79.8, 79.6, 72.5, 68.0, 57.3 (2C),45.8 (2C), 28.8, 28.7, 25.0, 24.7; MS (ES+) m/z 349.8 (M+1).

EXAMPLE 4.21 Synthesis of1′-[(1-ethyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(chloromethyl)-1-ethyl-1H-imidazol-3-iumchloride to replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-[(1-ethyl-1H-imidazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (57%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.34-6.95 (m, 4H), 6.41 (d, J=9.2 Hz, 1H), 6.38 (s, 1H), 5.04-4.90 (m,1H), 4.80-4.62 (m, 2H), 4.52-4.30 (m, 4H), 4.08-3.76 (m, 2H), 2.91 (t,J=8.6 Hz, 2H), 2.70-2.56 (m, 1H), 2.44-2.33 (m, 1H); ¹³C NMR (75 MHz,CDCl₃) δ178.0, 177.8, 161.5, 161.0 (2C), 143.5, 143.4, 132.5, 132.4,129.0, 128.9, 123.8, 123.7, 123.3, 121.0 (20), 120.3, 119.3, 119.2,110.3, 110.2, 92.9 (2C), 80.3 (2C), 79.8, 79.6, 72.5, 68.0, 57.3 (2C),45.8 (2C), 28.8, 28.7, 25.0, 24.7; MS (ES+) m/z 349.8.

EXAMPLE 4.22 Synthesis of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile

To a solution of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.97 g, 3.46 mmol) in 2-butanone (25 mL) were added cesium carbonate(3.39 g, 10.39 mmol) and α-bromo-m-tolunitrile (0.85 g, 4.33 mmol). Themixture was heated to reflux for 2 h, cooled to ambient temperature, andfiltered. The solid was washed with ethyl acetate. The filtrate wasconcentrated in vacuo, the residue was purified by column chromatographywith ethyl acetate-hexanes (1:5-1:1), followed by recrystallization fromethyl acetate and diethyl ether to afford3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(1.26 g, 92%) as a colorless solid: mp 187-193° C.; ¹H NMR (300 MHz,CDCl₃) δ7.61-7.58 (m, 3H), 7.47-7.44 (m, 1H), 7.25-7.19 (m, 2H),7.07-7.03 (m, 1H), 6.73-6.71 (m, 1H), 6.43-6.41 (m, 2H), 5.11-4.70 (m,4H), 4.53 (d, J=9.0 Hz, 2H), 3.09-2.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ178.1, 162.0, 161.4, 141.5, 137.5, 132.6, 131.9, 131.6, 130.7, 129.9,128.9, 124.3, 123.9, 120.2, 119.9, 118.7, 118.4, 113.1, 108.8, 93.4,80.5, 72.5, 57.7, 43.4, 29.0; MS (ES+) m/z 394.8 (M+1).

EXAMPLE 4.23 Synthesis of4-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzonitrile

Following the procedure as described in EXAMPLE 4.22 and makingnon-critical variations using 4-(bromomethyl)benzonitrile to replaceα-bromo-m-tolunitrile,4-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzonitrilewas obtained (88%) as a colorless solid: mp 69-71° C.; ¹H NMR (300 MHz,CDCl₃) δ7.73-7.56 (m, 2H), 7.50-7.40 (m, 2H), 7.22-7.15 (m, 2H),7.10-7.00 (m, 1H), 6.75-6.66 (m, 1H), 6.47-6.38 (m, 2H), 4.99 (ABq, 2H),4.83 (ABq, 2H), 4.54 (t, J=8.6 Hz, 2H), 3.06-2.92 (m, 2H); MS (ES+) m/z395.0 (M+1).

EXAMPLE 4.24 Synthesis of4′-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-bromomethyl-2-cyanobiphenyl to replace2-(bromomethyl)tetrahydro-2H-pyran,4′-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrilewas obtained (81%) as a colorless solid: mp 192-194° C.; ¹H NMR (300MHz, CDCl₃) δ7.74 (d, J=7.7 Hz, 1H), 7.63 (ddd, J=7.6, 7.6, 1.1 Hz, 1H),7.58-7.39 (m, 6H), 7.27-7.15 (m, 2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.85(d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H), 5.12 (d, J=15.7 Hz, 1H),5.00 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H),4.53 (t, J=8.6 Hz, 2H), 3.09-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ178.0, 161.9, 161.4, 144.8, 142.1, 137.7, 133.9, 133.0, 132.8, 130.1,129.3, 128.9, 127.8, 124.0, 123.6, 120.2, 120.0, 119.0, 118.7, 111.1,109.3, 93.3, 80.7, 72.4, 57.8, 43.9, 29.1; MS (ES+) m/z 471.0 (M+1).

EXAMPLE 4.25 Synthesis of1′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using (S)-2-(benzyloxymethoxy)propyl4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (61%) as a colorless solid: mp 49-52° C.; ¹H NMR (300 MHz,CDCl₃,)(diastereomers) δ7.36-7.22 (m, 4H), 7.20-6.99 (m, 5H), 6.44 (d,J=12.8 Hz, 1H), 6.39 (s, 1H), 4.89-4.61 (m, 4H), 4.56-4.33 (m, 4H),4.28-4.13 (m, 1H), 3.96-3.70 (m, 2H), 3.03-2.70 (m, 2H), 1.29 (dd,J=6.1, 3.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ178.1,161.6 (2), 143.0 (2), 137.6 (2), 132.7 (2), 128.7 (2), 128.5, 127.8 (2),127.6 (2), 123.8 (2), 123.2 (2), 120.3 (2), 119.9 (2), 119.0, 109.6 (2),93.2 (2), 93.0 (2), 80.7 (2), 72.4 (2), 71.5 (2), 69.5 (2), 57.6 (2),46.2 (2), 29.0 (2), 18.3 (2); MS (ES+) m/z 479.9 (M+23).

EXAMPLE 4.26 Synthesis of1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (86%) as a colorless solid: mp 173-175° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.21 (dd, J=7.8, 7.8 Hz, 1H),7.16 (d, J=6.9 Hz, 1H), 7.02 (dd, J=7.5, 7.02 Hz, 1H), 6.86-6.80 (m,4H), 6.49 (s, 1H), 6.43 (s, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.94 (d, J=15.2Hz, 1H), 4.75 (d, J=15.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6Hz, 2H), 4.24 (s, 4H), 3.09-2.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ177.9, 161.9, 161.4, 143.8, 143.3, 142.3, 132.9, 129.1, 128.8, 123.9,123.4, 120.6, 120.4, 120.0, 119.1, 117.7, 116.5, 109.5, 93.3, 80.8,72.5, 64.45, 64.41, 57.8, 43.7, 29.2; MS (ES+) m/z 428.0 (M+1).

EXAMPLE 4.27 Synthesis of1′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(bromomethyl)-2,1,3-benzoxadiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (74%) as a colorless solid: mp 169-171° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.06 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.49 (dd, J=9.3,1.3 Hz, 1H), 7.28-7.14 (m, 2H), 7.12-6.98 (m, 2H), 6.46 (s, 1H), 6.40(s, 1H), 5.14-4.97 (m, 2H), 4.89 (d, J=9.5 Hz, 1H), 4.74 (d, J=9.5 Hz,1H), 4.57-4.35 (m, 2H), 3.04-2.82 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.9, 161.7, 161.2, 149.3, 148.9, 142.4, 141.8, 133.2, 132.7, 129.2,124.2, 123.8, 120.9, 120.4, 119.4, 117.3, 113.5, 109.8, 93.0, 80.4,72.6, 65.4, 57.4, 43.7, 28.8; MS (ES+) m/z 411.9 (M+1).

EXAMPLE 4.28 Synthesis of1′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(bromomethyl)-2,1,3-benzothiadiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (74%) as a colorless solid: mp 162-164° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.12-8.04 (m, 2H), 7.63 (dd, J=9.3, 1.5 Hz, 1H),7.27-7.14 (m, 2H), 7.09 (d, J=7.7 Hz, 1H), 7.00 (dd, J=7.5, 7.5 Hz, 1H),6.42 (s, 1H), 6.40 (s, 1H), 5.23-5.05 (m, 2H), 4.88 (d, J=9.5 Hz, 1H),4.73 (d, J=9.5 Hz, 1H), 4.55-4.38 (m, 2H), 3.04-2.82 (m, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ177.8, 161.7, 161.2, 154.7, 154.2, 142.5, 139.0,132.6, 130.2, 129.2, 124.2, 123.7, 122.3, 120.9, 120.4, 119.6, 119.3,109.9, 93.0, 80.3, 72.6, 57.5, 43.5, 28.8; MS (ES+) m/z 427.9 (M+1).

EXAMPLE 4.29 Synthesis of1′-[(4-benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-benzyl-2-(chloromethyl)morphine toreplace 2-(bromomethyl)tetrahydro-2H-pyran,1-[(4-benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (10%) as a colorless solid: mp 65-70° C.; ¹H NMR (300 MHz,CDCl₃) δ7.35-7.00 (m, 9H), 6.49-6.39 (m, 2H), 4.92-4.84 (m, 1H),4.69-4.49 (m, 3H), 3.93-3.42 (m, 7H), 3.02-2.54 (m, 4H), 2.22-2.00 (m,2H); MS (ES+) m/z 469.1 (M+1).

EXAMPLE 4.30 Synthesis of tert-butyl3-[(2′-oxo-5,6-dihydrospiro[benzo-[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using tert-butyl3-(bromomethyl)pyrrolidine-1-carboxylate to replace2-(bromomethyl)tetrahydro-2H-pyran, tert-butyl3-[(2′-oxo-5,6-dihydrospiro[benzo-[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylatewas obtained (85%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃)(diastereomers) δ7.30 (dd, J=7.5, 7.5 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H),7.07 (dd, J=7.2, 6.9 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.46 (s, 1H), 6.42(s, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6Hz, 2H), 3.95-3.44 (m, 3H), 3.41-3.27 (m, 1H), 3.24-3.13 (m, 1H),3.06-2.92 (m, 2H), 2.82-2.68 (m, 1H), 2.05-1.92 (m, 1H), 1.82-1.69 (m,1H), 1.46 (s, 9H), 0.93-0.85 (m, 1H); MS (ES+) m/z 485.3 (M+23).

EXAMPLE 4.31 Synthesis of tent-butyl(2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate

Following the procedure as described in EXAMPLE 4.22 and makingnon-critical variations using (S)-tert-butyl2-(tosyloxymethyl)pyrrolidine-1-carboxylate (Fuji, K., et al., J. Am.Chem. Soc. (1989), 111(20):7921-5) to replace α-bromo-m-tolunitrile,tert-butyl(2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylatewas obtained (80%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)(diastereomers) δ7.37-7.25 (m, 2H), 7.20-7.00 (m, 2H), 6.54-6.41 (m,2H), 4.96-4.88 (m, 1H), 4.70-4.64 (m, 1H), 4.534 (t, J=8.6 Hz, 1H),4.527 (t, J=8.6 Hz, 1H), 4.31-4.19 (m, 1H), 3.99-3.85 (m, 1H), 3.80-3.67(m, 1H), 3.49-3.22 (m, 2H), 3.05-2.91 (m, 2H), 2.10-1.77 (m, 4H), 1.48(s, 4.5H), 1.42 (s, 4.5H); MS (ES+) m/z 485.1 (M+23).

EXAMPLE 4.32 Synthesis of tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate to replace2-(bromomethyl)tetrahydro-2H-pyran, tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylatewas obtained (99%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30(ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5,7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.42 (s, 1H), 4.91(d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H),4.20-4.06 (m, 2H), 3.72 (dd, J=14.0, 7.5 Hz, 1H), 3.58 (d, J=14.0, 6.6Hz, 1H), 3.08-2.92 (m, 2H), 2.75-2.61 (m, 2H), 2.11-1.96 (m, 1H),1.73-1.60 (m, 2H), 1.45 (s, 9H), 1.33-1.22 (m, 2H); MS (ES+) m/z 499.2(M+23).

EXAMPLE 4.33 Synthesis of4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,4′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: mp 166-169° C.; ¹H NMR (300MHz, CDCl₃) δ7.29-7.18 (m, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.89 (d, J=7.82Hz, 1H), 6.74 (d, J=2.3 Hz, 1H), 6.45-6.34 (m, 2H), 5.11 (d, J=16.2 Hz,1H), 4.99 (d, J=9.2 Hz, 1H), 4.88 (d, J=9.2 Hz, 1H), 4.81 (d, J=16.2 Hz,1H), 4.52 (t, J=8.6 Hz, 2H), 2.98 (t, J=8.60 Hz, 2H); ¹³C NMR (75 MHz,CDCl₃) δ177.2, 162.2, 162.0, 151.6, 143.1, 141.8 (q, J=43.0 Hz), 131.6,130.0, 128.7, 124.6, 118.8 (q, J=267.1 Hz), 119.7, 118.4, 117.1, 112.7,109.5, 107.2, 92.9, 77.1, 72.4, 58.2, 37.1, 28.9; MS (ES+) m/z 461.9(M+1), 463.9 (M+1).

EXAMPLE 4.34 Synthesis of4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: mp 78-82° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.32-7.09 (m, 1H), 7.05-6.92 (m, 1H), 6.44 (s, 1H), 6.35 (s,1H), 4.96 (dd, J=9.1, 1.1 Hz, 1H), 4.85 (d, J=9.1 Hz, 1H), 4.51 (t,J=8.7 Hz, 1H), 4.31-4.16 (m, 1H), 4.00-3.59 (m, 1H), 2.98 (t, J=8.6 Hz,1H), 2.12-1.80 (m, 1H), 1.76-1.61 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆)δ178.0 (2), 162.1 (2), 162.0, 144.7, 131.1 (2), 129.8 (2), 128.7 (2),123.9, 119.4 (2), 118.4 (2), 117.5 (2), 108.1 (2), 92.9, 77.5, 76.9 (2),72.3, 68.2 (2), 58.1 (2), 44.9 (2), 29.1 (2), 29.0 (2), 25.6 (2); MS(ES+) m/z 397.9 (M+1), 399.9 (M+1).

EXAMPLE 4.35 Synthesis of4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (75%) as a colorless solid: mp 137-141° C.; ¹H NMR (300MHz, DMSO-d₆) (diastereomers) δ7.30-7.10 (m, 3H), 6.42-6.37 (m, 1H),6.32 (s, 1H), 4.88 (d, J=9.63 Hz, 1H), 4.70-4.63 (m, 1H), 4.46 (t, J=8.6Hz, 2H), 4.18-4.05 (m, 1H), 3.85-3.52 (m, 4H), 2.93 (t, J=8.5 Hz, 2H),2.01-1.67 (m, 3H), 1.64-1.49 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.5(2), 162.2, 161.8, 145.7, 130.9, 130.2 (2), 126.6, 119.9 (2), 119.0 (2),118.9 (2), 118.1, 92.5, 77.5, 76.3, 76.1, 72.5, 67.7 (2), 65.4, 58.7,44.5, 29.0 (2), 28.7, 25.5; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).

EXAMPLE 4.36 Synthesis of1′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran,1-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (64%) as a colorless solid: mp 134-137° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.15 (dd,J=7.2, 0.9 Hz, 1H), 7.03 (ddd, J=7.4, 7.4, 0.7 Hz, 1H), 6.89 (d, J=7.8Hz, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.62 (d,J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.14-4.09 (m, 2H), 3.89-3.80 (m, 1H),3.73-3.63 (m, 1H), 1.75-1.59 (m, 3H), 1.00 (d, J=6.3 Hz, 6H); ¹³C NMR(75 MHz, CDCl₃) δ177.3, 155.4, 144.6, 142.5, 138.3, 132.8, 128.9, 124.0,123.2, 121.3, 111.6, 108.6, 99.4, 80.2, 64.6, 64.0, 58.1, 38.9, 36.3,26.2, 22.7, 22.6; MS (ES+) m/z 366.3 (M+1); Anal. Calcd for C₂₂H₂₃NO₄:C, 72.31; H, 6.34; N, 3.83. Found: C, 72.21; H, 6.31; N, 3.55.

EXAMPLE 4.37 Synthesis oft-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and4-(bromomethyl)tetrahydro-2H-pyran to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 129-131° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ7.29 (ddd, J=7.9, 7.9, 1.3 Hz, 1H), 7.16 (d, J=7.5Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H),6.50 (s, 1H), 6.18 (s, 1H), 4.87 (d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz,1H), 4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 4.03-3.94 (m, 2H), 3.74 (dd,J=13.8, 7.7 Hz, 1H), 3.55 (dd, J=13.8, 7.1 Hz, 1H), 3.42-3.30 (m, 2H),2.20-2.03 (m, 1H), 1.66-1.56 (m, 2H), 1.53-1.40 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ177.8, 155.4, 144.7, 142.8, 138.4, 132.5, 128.9, 124.2,123.4, 121.1, 111.5, 108.7, 99.5, 80.4, 67.6, 67.5, 64.6, 64.0, 58.1,46.2, 34.0, 30.93, 30.86; MS (ES+) m/z 394.2 (M+1); Anal. Calcd forC₂₃H₂₃NO₅: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.15; H, 5.92; N,3.20.

EXAMPLE 4.38 Synthesis of1-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (45%) as a colorless solid: mp 158-166° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) (diastereomers) δ7.31-7.25 (m, 1H), 7.13 (d, J=7.5Hz, 1H), 7.08-7.00 (m, 2H), 6.48 (s, 1H), 6.24 (s, 0.5H), 6.22 (s,0.5H), 4.89 (d, J=9.0 Hz, 0.5H), 4.88 (d, J=9.0 Hz, 0.5H), 4.64 (d,J=9.0 Hz, 0.5H), 4.63 (d, J=9.0 Hz, 0.5H), 4.21-4.16 (m, 2H), 4.14-4.09(m, 2H), 4.01-3.93 (m, 1H), 3.91-3.82 (m, 1H), 3.74-3.63 (m, 2H),3.44-3.33 (m, 1H), 1.91-1.81 (m, 1H), 1.68-1.31 (m, 5H); ¹³C NMR (75MHz, CDCl₃) (diastereomers) δ177.89, 177.80, 155.30, 155.27, 144.61,143.25, 143.11, 138.34, 132.46, 132.35, 128.78, 128.73, 123.66, 123.64,123.19, 123.17, 121.51, 121.45, 111.76, 111.62, 109.90, 109.77, 99.41,99.36, 80.14, 75.75, 75.58, 68.57, 68.53, 64.63, 64.02, 58.08, 58.04,45.83, 45.77, 29.70, 29.57, 25.88, 23.13; MS (ES+) m/z 394.2 (M+1);Anal. Calcd for C₂₃H₂₃NO₅: C, 70.21; H, 5.89; N, 3.56. Found: C, 70.03;H, 5.97; N, 3.17.

EXAMPLE 4.39 Synthesis of1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (94%) as a colorless solid: mp 91-95° C. (dichloromethane);¹H NMR (300 MHz, CDCl₃) δ7.39 (d, J=7.8 Hz, 1H), 7.27 (ddd, J=7.7, 7.7,1.2 Hz, 1H), 7.14 (dd, J=7.2, 0.9 Hz, 1H), 7.05 (ddd, J=7.4, 7.4, 0.8Hz, 1H), 6.94 (s, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.12 (d, J=15.6 Hz,1H), 4.93 (d, J=15.6 Hz, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz,1H), 4.21-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.59 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ177.3, 155.4, 144.8, 141.9, 141.7, 138.5, 131.6, 129.3,124.8, 124.0, 123.8, 120.7, 119.5, 111.5, 110.7, 99.6, 80.3, 64.6, 64.0,58.1, 38.2, 31.0; MS (ES+) m/z 426.2 (M+1), 424.2 (M+1).

EXAMPLE 4.40 Synthesis of1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 2.28 and makingnon-critical variations using1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one,1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride was obtained (82%) as a colorless solid: 207-208° C.(hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ7.80 (s, 1H), 7.40 (d, J=7.8 Hz,1H), 7.31 (dd, J=7.8, 7.2 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.08 (dd,J=7.5, 7.2 Hz, 1H), 6.50 (s, 1H), 6.42 (s, 1H), 5.30 (s, 2H), 4.83 (d,J=9.6 Hz, 1H), 4.66 (d, J=9.6 Hz, 1H), 4.20-4.15 (m, 2H), 4.13-4.08 (m,2H), 3.70 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.0, 154.8, 144.2,141.8, 141.7, 137.9, 132.1, 128.6, 123.6, 123.5, 121.0, 120.9, 118.0,111.9, 109.8, 98.6, 79.9, 64.2, 63.6, 57.3, 35.8, 31.9; MS (ES+) m/z426.2 (M+1), 424.2 (M+1); Anal. Calcd for C₂₂H₁₈ClN₃O₄HCl.H₂O: C, 55.24;H, 4.43; N, 8.78. Found: C, 55.51; H, 4.18; N, 8.58.

EXAMPLE 4.41 Synthesis of1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: mp 208-209° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ8.58 (d, J=4.8 Hz, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7Hz, 1H), 7.28-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.89 (d, J=7.8Hz, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.21 (d, J=16.0 Hz, 1H), 4.97 (d,J=16.0 Hz, 1H), 4.96 (d, J=8.7 Hz, 1H), 4.68 (d, J=8.7 Hz, 1H),4.22-4.17 (m, 2H), 4.15-4.10 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6,155.6, 155.3, 149.6, 144.6, 142.2, 138.3, 137.1, 132.2, 128.9, 123.8,123.5, 122.8, 121.6, 121.1, 111.8, 109.6, 99.4, 80.2, 64.5, 63.9, 58.2,46.1; MS (ES+) m/z 387.2 (M+1).

EXAMPLE 4.42 Synthesis of1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 2.28 and makingnon-critical variations using1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzo-dioxine-8,3′-indol]-2′(1′H)-oneto replace1-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one,1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride was obtained (89%) as a pale yellow powder: mp 206-208° C.(hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ8.68 (dd, J=4.8, 0.9 Hz, 1H), 8.13(ddd, J=7.7, 7.7, 1.0 Hz, 1H), 7.65-7.58 (m, 2H), 7.26 (ddd, J=7.7, 7.7,1.1 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 7.07-7.01 (m, 2H), 6.51 (s, 1H),6.35 (s, 1H), 5.24 (d, J=17.1 Hz, 1H), 5.17 (d, J=17.1 Hz, 1H), 4.83 (d,J=9.3 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H), 4.21-4.16 (m, 2H), 4.14-4.09 (m,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.0, 154.7, 153.5, 146.2, 144.2,142.2, 141.2, 137.8, 131.9, 128.8, 124.2, 123.6, 123.23, 123.21, 121.2,111.7, 109.3, 98.7, 79.5, 64.2, 63.6, 57.3, 43.3; MS (ES+) m/z 387.2(M+1); Anal. Calcd for C₂₃H₁₈N₂O₄.HCl-0.3H₂O: C, 64.42; H, 4.62; N,6.53. Found: C, 64.72; H, 4.55; N, 6.13.

EXAMPLE 4.43 Synthesis of1-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(S)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,1-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (69%) as a colorless solid: mp 173-175° C. (methanol); ¹HNMR (300 MHz, CDCl₃) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-7.00 (m,3H), 6.49 (s, 1H), 6.24 (s, 1H), 4.88 (d, J=8.9 Hz, 1H), 4.63 (d, J=8.9Hz, 1H), 4.31-4.22 (m, 1H), 4.21-4.17 (m, 2H), 4.14-4.09 (m, 2H),3.99-3.67 (m, 4H), 2.09-1.66 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)(diastereomers) δ178.1, 177.9, 155.3, 144.6, 143.0, 142.9, 138.4, 132.4,132.3, 128.9, 128.8, 123.8, 123.7, 123.3, 121.4, 121.3, 111.7, 111.6,109.8, 109.5, 99.4, 80.3, 80.2, 77.1, 76.8, 68.35, 68.31, 64.6, 64.0,58.09, 58.06, 44.7, 29.4, 29.0, 25.9, 25.7; MS (ES+) m/z 380.2 (M+1).

EXAMPLE 4.44 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%) as a colorless solid: mp 174-176° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) (diastereomers) δ7.32-7.25 (m, 1H), 7.16-7.00 (m,3H), 6.49 (s, 1H), 6.24 (s, 1H), 4.88 (d, J=8.7 Hz, 1H), 4.63 (d, J=8.7Hz, 1H), 4.31-4.22 (m, 1H), 4.21-4.17 (m, 2H), 4.14-4.09 (m, 2H),3.99-3.67 (m, 4H), 2.09-1.82 (m, 3H), 1.78-1.66 (m, 1H); ¹³C NMR (75MHz, CDCl₃) (diastereomers) δ178.1, 177.9, 155.3, 144.6, 143.0, 142.9,138.4, 132.4, 132.3, 128.9, 128.8, 123.8, 123.7, 123.3, 121.4, 121.3,111.7, 111.6, 109.8, 109.5, 99.4, 80.29, 80.26, 77.1, 76.8, 68.4, 68.3,64.6, 64.0, 58.10, 58.08, 44.7, 29.4, 29.1, 25.9, 25.7; MS (ES+) m/z380.2 (M+1).

EXAMPLE 4.45 Synthesis of1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.30 g, 1.03 mmol), 2-(iodomethyl)-1,4-dioxane (0.31 g, 1.35 mmol) andcesium carbonate (0.52 g, 1.58 mmol) in 2-butanone (7 mL) was stirred atreflux under nitrogen for 4 h. Once cooled, the reaction was dilutedwith ethyl acetate and the suspension was filtered through Celite. Thefiltrate was concentrated under reduced pressure and the residue waspurified by flash column chromatography with dichloromethane/diethylether (14:1) to afford1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneas an inseparable mixture with unreacted lactam (0.36 g). A mixture ofthis material, benzyl bromide (0.12 mL, 1.00 mmol) and cesium carbonate(0.50 g, 1.55 mmol) in 2-butanone (7 mL) was then stirred at refluxunder nitrogen for 15 h. Work-up as described above and purified byflash column chromatography with (hexanes/ethyl acetate) (2:1, increasedto 1:1) afforded1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.24 g, 58%) as a colorless solid, along with1′-benzyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.09 g, 24%) as a colorless solid. Characterization for1-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one:mp 160-165° C. (hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers)δ7.26-7.34 (m, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.01-7.09 (m, 2H), 6.49 (s,1H), 6.24 (s, 0.5H), 6.21 (s, 0.5H), 4.88 (d, J=8.9 Hz, 0.5 Hz), 4.87(d, J=8.9 Hz, 0.5H), 4.64 (d, J=8.9 Hz, 0.5H), 4.63 (d, J=8.9 Hz, 0.5H),4.22-4.16 (m, 2H), 4.15-4.09 (m, 2H), 3.99-3.78 (m, 4H), 3.76-3.55 (m,4H), 3.47-3.37 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ177.9,177.8, 156.3, 155.3, 144.71, 144.69, 142.72, 142.66, 138.42, 138.39,132.4, 132.3, 128.91, 128.85, 123.9, 123.8, 123.5, 121.3, 121.1, 111.7,111.6, 109.6, 109.4, 99.49, 99.46, 80.2, 80.0, 73.32, 73.29, 69.4, 69.2,66.8, 66.7, 66.52, 66.48, 64.6, 64.0, 58.1, 58.0, 41.85, 41.76; MS (ES+)m/z 396.2 (M+1).

EXAMPLE 4.46 Synthesis of1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and3,4-dimethoxybenzyl bromide (Oguri, T., et al., Chem. Pharm. Bull.(1977), 25:2287-91) to replace 2-(bromomethyl)tetrahydro-2H-pyran,1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (100%) as a colorless solid: mp 209-211° C.(hexanes/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ7.23-7.14 (m, 2H),7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.80 (m, 4H), 6.51 (s, 1H), 6.21 (s,1H), 5.09 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.68 (d, J=15.3Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.13-4.08 (m, 2H),3.86 (s, 3H), 3.84 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 155.3,149.5, 148.8, 144.7, 142.2, 138.4, 132.4, 128.9, 128.4, 124.0, 123.5,121.3, 120.0, 111.5, 111.2, 110.5, 109.5, 99.6, 80.1, 64.6, 64.0, 58.2,56.02, 55.99, 44.1; MS (ES+) m/z 446.0 (M+1).

EXAMPLE 4.47 Synthesis of1′-(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and3,5-dimethoxybenzyl bromide to replace2-(bromomethyl)tetrahydro-2H-pyran,1′(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (97%) as a colorless solid: mp 192-195° C. (diethylether/hexanes); ¹F1 NMR (300 MHz, CDCl₃) δ7.23-7.15 (m, 2H), 7.02 (dd,J=7.5, 7.5 Hz, 1H), 6.81 (d, J=7.5 Hz, 1H), 6.51 (s, 1H), 6.47 (d, J=1.8Hz, 2H), 6.37 (t, J=1.8 Hz, 1H), 6.25 (s, 1H), 5.04 (d, J=15.5 Hz, 1H),4.95 (d, J=9.0 Hz, 1H), 4.72 (d, J=15.5 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H),4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H), 3.76 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ177.7, 161.3, 155.4, 144.7, 142.2, 138.5, 138.2, 132.3, 129.0,123.9, 123.5, 121.2, 111.6, 109.5, 105.4, 99.8, 99.6, 80.2, 64.6, 64.0,58.2, 55.5, 44.3; MS (ES+) m/z 446.0 (M+1).

EXAMPLE 4.48 Synthesis of1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and6-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al.,Tetrahedron, (2001), 57:8297-304) to replace2-(bromomethyl)tetrahydro-2H-pyran,1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (100%) as a colorless solid: mp 120-123° C.(hexanes/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ7.20 (ddd, J=7.8, 7.5,1.2 Hz, 1H), 7.15 (dd, J=7.4, 0.8 Hz, 1H), 7.01 (ddd, J=7.5, 7.4, 0.7Hz, 1H), 6.85-6.79 (m, 4H), 6.50 (s, 1H), 6.24 (s, 1H), 4.93 (d, J=8.7Hz, 1H), 4.92 (d, J=15.5 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H), 4.65 (d,J=8.7 Hz, 1H), 4.23 (s, 4H), 4.22-4.17 (m, 2H), 4.14-4.10 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ177.5, 155.4, 144.7, 143.8, 143.3, 142.3, 138.4,132.4, 129.0, 128.9, 123.9, 123.4, 121.2, 120.5, 117.8, 116.5, 111.8,109.5, 99.5, 80.4, 64.6, 64.44, 64.41, 64.0, 58.2, 43.8; MS (ES+) m/z444.0 (M+1).

EXAMPLE 4.49 Synthesis of(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using(R)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (92%) as a colorless solid: mp 64-68° C. (methanol/water);¹H NMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.8, 7.7, 1.0 Hz, 1H), 7.18 (d,J=7.2 Hz, 1H), 7.07 (dd, J=7.5, 7.2 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H),6.76-6.72 (m, 1H), 6.50 (s, 1H), 6.38 (d, J=3.3 Hz, 1H), 6.19 (s, 1H),5.06 (d, J=16.5 Hz, 1H), 4.89 (d, J=16.5 Hz, 1H), 4.90 (d, J=9.0 Hz,1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.14-4.09 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz),141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (d, J=267 Hz),112.8 (d, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1,37.1; MS (ES+) m/z 443.9 (M+1).

EXAMPLE 4.50 Synthesis of(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using(S)-(2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 53-56° C. (methanol/water);¹H NMR (300 MHz, CDCl₃) δ7.30 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.2Hz, 1H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.74 (dd,J=2.1, 0.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.19 (s, 1H),5.06 (d, J=16.2 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.2 Hz,1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz),141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (q, J=267 Hz),112.8 (q, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1,37.1; MS (ES+) m/z 443.9 (M+1).

EXAMPLE 4.51 Synthesis of(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 144-146° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.59 (dd, J=5.1, 0.6 Hz, 1H),7.73 (ddd, J=7.8, 7.5, 1.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.22 (ddd, J=7.7,7.7, 1.3 Hz, 1H), 7.17 (dd, J=7.4, 0.9 Hz, 1H), 7.03 (ddd, J=7.5, 7.5,0.9 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.29 (s, 1H), 5.26(d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H),4.68 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H), 4.15-4.11 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.7, 155.4, 155.3, 148.6, 144.8, 142.0, 138.4, 138.2,132.2, 129.0, 124.0, 123.7, 123.3, 122.3, 121.1, 111.8, 109.7, 99.5,80.3, 64.6, 64.0, 58.2, 45.5; MS (ES+) m/z 387.0 (M+1).

EXAMPLE 4.52 Synthesis of1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 198-200° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.59 (d, J=4.8 Hz, 1H), 7.71(dd, J=7.8, 7.5 Hz, 1H), 7.32-7.15 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz,1H), 6.94 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 6.17 (s, 1H), 5.27 (d, J=15.6Hz, 1H), 5.01 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.70 (d, J=9.0Hz, 1H), 4.49 (td, J=8.7, 0.7 Hz, 2H), 3.15 (t, J=8.7 Hz, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.7, 155.3, 155.2, 154.9, 148.6, 142.1, 138.3, 132.1,129.1, 128.9, 127.6, 124.0, 123.7, 123.3, 122.3, 109.7, 107.2, 104.0,80.1, 71.8, 58.6, 45.5, 30.4; MS (ES+) m/z 370.9 (M+1).

EXAMPLE 4.53 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-onewas obtained (57%) as an off-white solid: mp 151-156° C. (diethylether); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ7.32-7.26 (m, 1H),7.16-7.02 (m, 3H), 6.40 (s, 1H), 6.38 (s, 1H), 4.89 (d, J=9.0 Hz, 1H),4.644, 4.640 (d, J=9.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.11 (dd, J=5.4, 4.8Hz, 2H), 3.99-3.69 (m, 4H), 2.63-2.52 (m, 2H), 2.10-1.85 (m, 5H),1.79-1.67 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ178.3,178.2, 160.2, 156.3, 143.0, 132.8, 132.7, 128.8, 128.7, 123.88, 123.86,123.82, 123.76, 123.3, 121.1, 121.0, 115.24, 115.20, 109.7, 109.5, 98.9,80.43, 80.40, 77.1, 77.0, 68.4, 68.3, 66.7, 57.8, 57.7, 44.8, 44.7,29.4, 29.1, 25.8, 25.7, 24.8, 24.7, 22.4; MS (ES+) m/z 378.1 (M+1).

EXAMPLE 4.54 Synthesis of1-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,1-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (97%) as a colorless solid: mp 162-164° C.(water/methanol); ¹H NMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.8, 7.8, 1.2Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d,J=7.8 Hz, 1H), 6.76-6.73 (m, 1H), 6.60 (s, 1H), 6.39 (d, J=3.3 Hz, 1H),6.32 (s, 1H), 5.07 (d, J=16.4 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.89 (d,J=16.4 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.29-4.21 (m, 1H), 4.14-4.02 (m,2H), 3.99-3.91 (m, 1H), 2.23-2.00 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ177.1, 156.8, 153.2, 152.1 (q, J=1.3 Hz), 146.4, 141.8 (q, J=42.9 Hz),141.4, 132.1, 129.1, 124.2, 124.0, 122.9, 118.9 (q, J=267 Hz), 116.1,112.8 (q, J=2.7 Hz), 109.4, 109.0, 103.6, 80.4, 70.91, 70.90, 58.0,37.1, 32.3; MS (ES+) m/z 457.9 (M+1).

EXAMPLE 4.55 Synthesis of1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (90%) as a colorless solid: mp 122-123° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.59 (d, J=4.8 Hz, 1H), 7.71(ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d,J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71(d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m,1H), 2.22-2.02 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 156.8, 155.4,153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1,123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2;MS (ES+) m/z 401.0 (M+1).

EXAMPLE 4.56 Synthesis of2-methyl-1′-(3-methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran,2-methyl-t-(3-methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 137-138° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.60 (d, J=8.6 Hz, 1H), 7.32-7.27 (m,1H), 7.13-7.08 (m, 1H), 7.03-6.92 (m, 3H), 5.03 (d, J=8.8 Hz, 1H), 4.78(d, J=8.8 Hz, 1H), 4.12-4.01 (m, 1H), 3.71-3.60 (m, 1H), 2.56 (s, 3H),1.93-1.61 (m, 3H), 1.06-1.00 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ176.8,169.3, 160.4, 149.4, 142.8, 132.9, 129.1, 128.7, 123.6, 122.8, 122.2,120.4, 108.6, 108.4, 81.1, 58.2, 39.2, 36.1, 26.0, 23.0, 22.5, 20.3; MS(ES+) m/z 378.5 (M+1).

EXAMPLE 4.57 Synthesis of2-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2″(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and4-(bromomethyl)tetrahydropyran to replace2-(bromomethyl)tetrahydro-2H-pyran,2-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp 186-187° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.66-7.60 (m, 1H), 7.34-7.27 (m, 1H),7.13-7.07 (m, 1H), 7.06-6.91 (m, 3H), 5.04-4.97 (m, 1H), 4.78-4.72 (m,1H), 4.07-3.93 (m, 3H), 3.52-3.35 (m, 3H), 2.52 (s, 3H), 2.32-2.15 (m,1H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.57-1.42 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.4, 169.3, 160.6, 149.2, 143.1, 132.7, 129.1, 128.7,123.7, 123.0, 122.3, 119.9, 108.7, 108.5, 81.5, 67.9, 62.4, 58.1, 46.6,34.3, 30.9, 20.2, 14.6; MS (ES+) m/z 407.0 (M+1).

EXAMPLE 4.58 Synthesis of2-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,2-methyl-1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-onewas obtained (52%) as a colorless solid: mp 188-190° C. (ethyl acetate);¹H NMR (300 MHz, CDCl₃) δ7.37-7.30 (m, 2H), 7.23-7.05 (m, 2H), 6.98-6.93(m, 2H), 6.00-5.93 (m, 1H), 5.43-5.38 (m, 1H), 4.42-4.26 (m, 1H),4.05-3.75 (m, 4H), 2.35-2.33 (m, 3H) 2.09-1.79 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ175.6, 175.3, 164.4, 164.3, 151.2, 151.1, 146.2, 146.1, 144.9,144.6, 138.7, 138.6, 130.5, 130.4, 129.6, 124.6, 124.4, 123.0 (2C),114.0, 113.9, 111.8, 111.6, 110.6, 110.5, 110.3, 109.8, 88.7, 88.4,76.1, 76.0, 68.5, 68.3, 44.7, 44.4, 29.8, 28.9, 26.2, 25.7, 14.7, 14.6;MS (ES+) m/z 414.9 (M+39).

EXAMPLE 4.59 Synthesis of1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H-3H)-dione

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dioneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dionewas obtained (69%) as an off-white solid: mp 79-81° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.16-7.04 (m,3H), 6.63-6.62 (m, 1H), 6.39-6.32 (m, 1H), 4.96-4.92 (m, 1H), 4.72-4.67(m, 1H), 4.54 (s, 2H), 4.37-4.26 (m, 1H), 3.98-3.85 (m, 2H), 3.82-3.70(m, 2H), 3.15 (s, 3H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.65(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.7 (2C), 163.9 (2C), 157.4, 157.3,146.9 (2C), 143.1, 142.6, 132.2, 131.9, 129.2, 129.1, 124.4 (2C), 123.8(2C), 123.5, 123.1, 122.8, 109.8, 109.7, 109.6, 100.1 (2C), 80.8, 80.6,76.9, 76.2, 68.4, 68.2, 67.7, 58.1 (2C), 44.9, 44.6, 29.3, 29.1, 28.5,28.4, 25.7 (2C); MS (ES+) m/z 429.1 (M+23), 407.1 (M+1).

EXAMPLE 4.60 Synthesis of1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dione

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using1-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dioneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-g][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,1′H)-dionewas obtained (32%) as a colorless solid: mp>250° C. (toluene/hexanes);¹H NMR (300 MHz, CDCl₃) δ7.38-7.29 (m, 1H), 7.17-7.03 (m, 3H), 6.90-6.85(m, 1H), 6.40-6.28 (m, 1H), 4.99-4.92 (m, 1H), 4.75-4.67 (m, 1H),4.36-4.25 (m, 1H), 4.01-3.67 (m, 4H), 3.25-3.21 (m, 3H), 2.14-1.85 (m,3H), 1.79-1.65 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 157.0, 156.9,155.0, 143.5 (2C), 143.1, 142.6, 132.2, 131.9, 129.3, 129.2, 126.2,124.1, 123.8, 123.6, 109.8, 109.8, 103.1, 103.0, 94.7 (2C), 80.5, 80.4,77.1, 76.3, 68.4, 68.2, 58.2 (2C), 45.0, 44.7, 29.3, 29.2, 28.3, 28.2,25.7; MS (ES+) m/z 393.0 (M+1).

EXAMPLE 4.61 Synthesis of6-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,6-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: mp 151-153° C.; ¹H NMR (300MHz, CDCl₃) δ7.27 (dd, J=7.7, 7.7 Hz, 1H), 7.15-6.98 (m, 3H), 6.48 (s,1H), 6.44 (s, 1H), 4.90 (d, J=8.9 Hz, 1H), 4.65 (dd, J=8.9, 2.3 Hz, 1H),4.32-4.21 (m, 1H), 3.99-3.61 (m, 4H), 3.78 (s, 3H), 2.10-1.63 (m, 4H),1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.3 (2), 160.3, 159.1, 142.9(2), 132.6 (2), 128.7 (2), 124.2 (2), 123.7 (2), 119.5 (2), 119.2 (2),109.5 (2), 93.7, 80.4 (2), 77.0 (2), 68.2 (2), 57.9, 55.5, 44.6 (2),29.1 (2), 25.6 (2), 15.9 (2); MS (ES+) m/z 366.3 (M+1).

EXAMPLE 4.62 Synthesis of6-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,6-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 142-144° C.; ¹H NMR (300MHz, CDCl₃) δ 8.56 (d, J=4.8 Hz, 1H), 7.67-7.60 (m, 1H), 7.28-7.11 (m,4H), 7.00 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.50 (s, 2H),5.09 (ABq, 2H), 4.84 (ABq, 2H), 3.79 (s, 3H), 2.00 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ178.0, 160.3, 159.2, 155.7, 149.5, 142.5, 142.2, 137.1,132.6, 128.7, 124.3, 123.8, 123.5, 122.8, 121.7, 119.5, 119.2, 109.5,93.8, 80.3, 58.0, 46.1, 22.6, 16.0; MS (ES+) m/z 373.3 (M+1).

EXAMPLE 4.63 Synthesis of6-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,6-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 180-182° C.; ¹H NMR (300MHz, CDCl₃) δ 7.28 (dd, J=7.8, 7.8 Hz, 1H), 7.13-6.97 (m, 3H), 6.47 (s,1H), 6.43 (d, J=4.3 Hz, 1H), 4.91 (dd, J=8.9, 2.1 Hz, 1H), 4.66 (dd,J=8.9, 3.3 Hz, 1H), 4.02-3.59 (m, 4H), 3.79 (s, 3H), 3.43-3.31 (m, 1H),1.99 (s, 3H), 1.92-1.77 (m, 1H), 1.71-1.26 (m, 5H); MS (ES+) m/z 380.4(M+1).

EXAMPLE 4.64 Synthesis of5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,5-fluoro-6-methoxy-1-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (99%) as a colorless solid: mp 131-133° C.; ¹H NMR (300MHz, CDCl₃) δ 7.31-7.24 (m, 1H), 7.13-6.98 (m, 3H), 6.61-6.55 (m, 1H),6.47-6.39 (m, 1H), 4.96-4.89 (m, 1H), 4.71-4.63 (m, 1H), 4.00-3.76 (m,5H), 3.73-3.59 (m, 2H), 3.42-3.30 (m, 1H), 1.91-1.79 (m, 1H), 1.70-1.27(m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 177.4, 157.10, 157.08, 157.05,157.03, 149.2, 149.0, 148.8, 146.1, 143.2, 143.0, 131.9, 131.8, 128.9,128.8, 123.52, 123.50, 123.18, 123.15, 119.4, 119.3, 119.2, 110.6,110.5, 110.3, 110.2, 109.9, 109.8, 96.2, 80.4, 75.6, 75.4, 68.4, 68.3,57.96, 57.95, 57.92, 56.4, 45.7, 45.6, 29.5, 29.4, 25.7, 23.0; MS (ES+)m/z 384.2 (M+1).

EXAMPLE 4.65 Synthesis of5-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and2 (bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)tetrahydro-2H-pyran,5-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (77%) as a colorless solid: mp 142-144° C.; ¹H NMR (300MHz, CDCl₃) δ 8.59-8.53 (m, 1H), 7.65 (ddd, J=7.7, 7.7, 1.7 Hz, 1H),7.28-7.10 (m, 4H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H),6.60 (d, J=6.8 Hz, 1H), 6.52 (d, J=10.1 Hz, 1H), 5.20 (d, J=15.8 Hz,1H), 5.03-4.90 (m, 2H), 4.72 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); ¹³C NMR(75 MHz, CDCl₃) δ177.3, 157.2 (d), 155.4, 149.6, 149.3, 149.1, 149.0,146.1, 142.1, 137.1, 131.8, 129.0, 123.8, 123.6, 122.8, 121.6, 119.0(d), 110.7, 110.4, 109.6, 96.3, 80.5, 58.1, 56.4, 46.0; MS (ES+) m/z377.2 (M+1).

EXAMPLE 4.66 Synthesis of5-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,5-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (42%) as a colorless solid: mp 106-116° C.; ¹H NMR (300MHz, CDCl₃) δ7.28 (dd, J=7.6, 7.6 Hz, 1H), 7.14-6.98 (m, 3H), 6.58 (d,J=6.8 Hz, 1H), 6.49-6.40 (m, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0Hz, 1H), 4.31-4.19 (m, 1H), 3.98-3.64 (m, 7H), 2.09-1.80 (m, 3H),1.76-1.61 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 177.5, 157.1, 149.3,149.1, 148.9, 146.1, 142.8, 131.9, 131.7, 129.0, 128.9, 123.7, 123.6,123.3, 119.3, 119.2, 110.6, 110.5, 110.3, 110.2, 109.8, 109.6, 96.3,80.6, 76.7, 68.2, 68.1, 58.0, 56.4, 44.6, 29.2, 29.0, 25.7, 25.5; MS(ES+) m/z 370.2 (M+1).

EXAMPLE 4.67 Synthesis of1′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, andbenzylbromide to replace 2-(bromomethyl)tetrahydro-2H-pyran,1-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (86%) as a colorless solid: mp 160-162° C.; ¹H NMR (300MHz, CDCl₃) δ7.39-7.26 (m, 5H), 7.20 (ddd, J=7.6, 7.6, 1.2 Hz, 1H),7.16-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.61 (d,J=6.8 Hz, 1H), 6.43 (d, J=10.1 Hz, 1H), 5.05 (d, J=15.5 Hz, 1H), 4.99(d, J=9.0 Hz, 1H), 4.83 (d, J=15.5 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 3.86(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 182.3, 173.3, 166.3, 165.6, 147.9,137.5, 133.7, 128.5, 128.0, 126.1, 124.9, 124.6, 114.2, 97.5, 84.9,77.3, 62.0, 47.6, 33.5; MS (ES+) m/z 376.0 (M+1).

EXAMPLE 4.68 Synthesis of6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)tetrahydro-2H-pyran,6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless liquid: ¹H NMR (300 MHz, CDCl₃)(diastereomers) δ7.32-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.61 (d, J=8.1Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=8.1, 2.1 Hz, 1H), 4.94 (d,J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.00-3.66 (m,4H), 3.77 (s, 3H), 2.10-1.66 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)(diastereomers) δ178.0, 177.9, 162.0, 161.4, 142.9, 142.8, 132.4, 132.3,128.7, 128.6, 123.6, 123.5 (2C), 123.4, 123.2, 121.0, 120.9, 109.6,109.3, 107.4 (2C), 96.5, 80.5, 80.4, 76.8, 76.7, 68.2, 68.1, 57.5, 55.5,44.5 (2C), 29.2, 28.9, 25.6, 25.5; MS (ES+) m/z 352.1 (M+1).

EXAMPLE 4.69 Synthesis of6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.3 g, 4.3 mmol) in2-butanone (40.0 mL) was added cesium carbonate (4.2 g, 12.9 mmol) and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (1.4 g, 5.4mmol). The reaction was refluxed for 16 h, filtered and concentrated invacuo to dryness. The residue was purified by flash chromatography with25% ethyl acetate in hexanes to afford6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.75 g, 100%) as a colorless solid: MS (ES+) m/z 400.0 (M+1), 402.0(M+1).

EXAMPLE 4.70 Synthesis of1-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,acetone to replace butanone, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace2-(bromomethyl)tetrahydro-2H-pyran,1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-onewas obtained (43%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.36-6.93 (m, 4H), 6.76-6.70 (m, 1H), 6.38 (d, J=3.5 Hz, 1H), 6.36 (s,1H), 6.21 (s, 1H), 4.98 (ABq, 2H), 4.80-4.69 (m, 1H), 4.45 (t, J=8.6 Hz,2H), 4.36-4.28 (m, 1H), 2.92 (t, J=8.5 Hz, 2H), 2.23-2.16 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ179.3, 160.6, 155.5, 152.2, 152.1, 141.8, 141.6,141.3, 135.2, 128.3, 124.1, 123.5, 123.5, 120.6, 120.4, 117.0, 112.6(2C), 112.5 (2C), 112.1, 109.1, 108.6, 98.6, 71.8, 62.0, 47.8, 36.7,32.4, 28.8; MS (ES+) m/z 441.7 (M+1).

EXAMPLE 4.71 Synthesis of1′-[4-(methylsulfanyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4.22 and makingnon-critical variations using (4-(bromomethyl)phenyl)(methyl)sulfane toreplace α-bromo-m-tolunitrile,1′-[4(methylsulfanyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (61%) as a colorless solid: MS (ES+) m/z: 416.2 (M+1).

EXAMPLE 4.72 Synthesis of1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using (R)-3-bromomethyl-2-pyrrolidinone toreplace 2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: mp 121-130° C.; ¹H NMR (300MHz, CD₃OD) δ7.34 (dd, J=7.6, 7.6 Hz, 1H), 7.22-7.06 (m, 4H), 6.48 (d,J=1.9 Hz, 1H), 6.15 (d, J=9.3 Hz, 1H), 5.82 (d, J=1.4 Hz, 2H), 4.86-4.81(m, 2H), 4.64 (dd, J=9.3, 3.8 Hz, 1H), 4.13-4.06 (m, 1H), 3.85-3.83 (m,2H), 2.43-2.18 (m, 2H), 2.00-1.88 (m, 1H); ¹³C NMR (75 MHz, CD₃OD)δ177.9, 177.4, 177.3, 154.7, 154.6, 147.5, 147.4, 141.2, 140.8, 140.8136.0, 130.8, 130.6, 127.3 127.2, 127.0, 126.3, 123.4, 122.0, 121.9,121.9 118.0, 117.8, 107.4, 101.1, 100.0, 99.9, 91.3, 91.3, 78.8, 78.7,56.8 (2C), 51.4, 51.2, 43.2 (2C), 27.6, 22.6, 18.6; MS (ES+) m/z 401.2(M+23), 379.2 (M+1).

EXAMPLE 4.73 Synthesis of(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using chloroacetonitrile to replace2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrilewas obtained (61%) as a colorless solid: mp 170-172° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.38 (dt, J=7.7, 1.2 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H),7.20 (d, J=7.3 Hz, 1H), 7.11 (dt, J=7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 6.21(s, 1H), 5.89 (d, J=1.5 Hz, 2H), 4.94 (ABq, J=17.9 Hz, 2H), 4.73 (ABq,J=9.5 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 155.8, 148.9, 142.232,141.0, 131.9, 129.4, 124.3, 124.3, 119.8, 116.0, 109.7, 103.5, 101.9,93.8, 80.1, 57.8, 28.8; MS (ES+) m/z 321.3 (M+1).

EXAMPLE 4.74 Synthesis of7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′d]furan-3,3′-indol]-2″(1′H)-one,7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (43%) as a colorless solid: mp 95-98° C.; ¹H NMR (300 MHz,CDCl₃) δ7.59 (d, J=8.1 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 7.15 (dd, J=7.8,7.8 Hz, 1H), 6.69 (d, J=3.2 Hz, 1H), 6.50 (s, 1H), 6.23 (d, J=3.0 Hz,1H), 6.10 (s, 1H), 5.86 (d, J=3.0 Hz, 2H), 5.23 (ABq, 2H), 4.78 (ABq,2H); ¹³C NMR (75 MHz, CDCl₃) δ178.6, 156.0, 152.2, 149.3, 142.7, 141.4(q), 139.1, 135.1, 127.9, 127.0 (m), 122.9 (d), 121.1 (d), 119.3 (d),118.7, 113.4 (q), 112.5, 108.2, 102.8, 101.7, 93.7, 80.8, 56.9, 39.4; MS(ES+) m/z 498.4 (M+1).

EXAMPLE 4.75 Synthesis of1-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-chloro-5-(chloromethyl)thiophene toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 165-166° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.66 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.24(dd, J=7.8, 7.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.80 (d, J=3.8 Hz, 1H),6.70 (s, 1H), 6.22 (s, 1H), 5.91 (d, J=4.4 Hz, 2H), 5.09 (ABq, 2H), 4.78(ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.9, 156.2, 149.2, 142.4, 139.9(2C), 138.7, 135.4, 129.1, 127.4, 127.2, 126.9, 125.9, 123.9, 119.4,111.5, 103.5, 102.0, 93.9, 80.7, 56.5, 42.3; MS (ES+) m/z 481.2 (M+1),479.9 (M+1).

EXAMPLE 4.76 Synthesis of1′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-chloromethyl-2-(isopropyl)thiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (51%) as a colorless solid: mp 101-103° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.61 (d, J=8.1 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.23 (ddJ=7.8, 7.8 Hz, 1H), 7.18 (s, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 5.91 (s,2H), 5.08 (ABq, 2H), 4.77 (ABq, 2H), 3.21-3.16 (m, 1H), 1.22 (d, J=6.9Hz, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.7, 177.4, 156.0, 150.7, 149.0,142.3, 140.7, 135.6, 128.7, 125.7, 124.5 (d), 123.6, 119.8, 113.3, 111.5(m), 103.9, 101.9, 93.8, 80.8, 56.6, 43.3, 32.8, 23.3; MS (ES+) m/z489.4 (M+1).

EXAMPLE 4.77 Synthesis of1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-chloromethyl-2-isopropyloxazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (11%) as a colorless solid: mp 75-77° C.; ¹H NMR (300 MHz,CDCl₃) δ7.42 (s, 1H), 7.26 (dd, J=7.4, 7.4 Hz, 1H), 7.15 (d, J=7.3 Hz,1H), 7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.15 (s, 1H), 5.83 (d, J=4.2 Hz,2H), 4.83 (ABq, 2H), 4.78 (ABq, 2H), 3.10-2.95 (m, 1H), 1.30 (d, J=7.0Hz, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.3, 169.4, 155.8, 148.9, 142.3,141.8, 135.3, 135.1, 132.2, 128.9, 123.8, 123.5, 119.5, 109.6, 103.1,101.5, 93.6, 80.3, 58.2, 36.6, 28.5, 20.4, 20.3; MS (ES+) m/z 405.4(M+1).

EXAMPLE 4.78 Synthesis of tert-butyl[1-cyclopropyl-3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]carbamate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using tert-butyl-3-bromomethyl-1-cyclopropylcarbamate to replace 2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,tert-butyl[1-cyclopropyl-3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]carbamatewas obtained (91%) as a fluffy yellow solid: ¹H NMR (300 MHz, CDCl₃)δ7.28 (dd, J=7.7, 7.7 Hz, 1H), 7.13 (d, J=6.9 Hz, 1H), 7.02 (dd, J=7.2,7.2 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.11 (d, J=4.9 Hz,1H), 5.83 (d, J=5.5 Hz, 2H), 4.88 (dd, J=8.9, 7.0, Hz, 1H), 4.69 (br,1H), 4.62 (dd, J=8.9, 1.7 Hz, 1H), 3.93-3.73 (m, 2H), 2.99 (br, 1H),2.14-1.81 (m, 2H), 1.30 (s, 9H), 0.95-0.80 (m, 1H), 0.58-0.19 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.3, 177.3, 155.9, 155.7, 155.6, 148.8,142.3, 142.2, 132.4, 129.0, 123.9, 123.3, 119.5, 119.4, 108.6, 103.1,103.0, 101.5, 93.6, 80.4 (2C), 65.9, 58.2, 37.8, 37.5, 32.9, 32.7, 28.4,16.1 (2C), 15.3, 3.9, 3.8, 3.0, 2.9; MS (ES+) m/z 501.3, (M+23), 479.28(M+1), 423.2 (M−56), 379.3 (M−100).

EXAMPLE 4.79 Synthesis of1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(methylthio)benzyl bromide to replace2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (86%) as a colorless solid: mp 128-130° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.28-7.19 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.00 (d, J=7.5Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.68 (s, 1H), 6.14 (s, 1H), 5.89 (d,J=1.9 Hz, 2H), 4.87-4.79 (m, 3H), 4.67 (d, J=9.3 Hz, 1H), 2.40 (s, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ177.3, 155.9, 148.8, 142.6, 142.2, 137.8,133.3, 132.1, 129.3, 128.4, 126.6, 124.2, 123.6, 120.1, 109.9, 103.3,101.9, 93.8, 80.4, 57.9, 43.2, 15.1; MS (ES+) m/z 418.1 (M+1).

EXAMPLE 4.80 Synthesis of3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile

Following the procedure as described in PREPARATION 44 and makingnon-critical variations using 3-bromopropionitrile to replaceα-bromo-m-tolunitrile, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrilewas obtained (86%) as a colorless solid: mp 200-202° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz,1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66(s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H),4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1,119.1, 109.8 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z335.1 (M+1).

EXAMPLE 4.81 Synthesis of1′-[(2-bromo-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-bromo-(5-bromomethyl)thiazole to replace2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[(2-bromo-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (94%) as a colorless solid: mp 215-217° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.81 (s, 1H), 7.34-7.24 (m, 2H), 7.15 (d, J=7.2 Hz, 1H),7.03 (ddd, J=7.3, 7.3, 1.3 Hz, 1H), 6.67 (s, 1H), 6.13 (s, 1H), 5.89 (d,J=3.9 Hz, 2H), 5.11 (s, 2H), 4.69 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.0, 155.9, 148.9, 142.9, 142.2, 141.7, 138.2, 136.4, 132.1, 129.4,124.3, 123.9, 119.9, 109.7, 103.4, 101.9, 93.8, 80.2, 57.8, 36.3; MS(ES+) m/z 458.9 (M+1), 456.9 (M+1).

EXAMPLE 4.82 Synthesis of1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using5-(chloromethyl)-4-(trifluoromethyl)thiazol-2-amine to replace2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2″(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (4.0%) as a colorless solid: mp 165-167° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.39 (br, 2H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d,J=6.7 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H),6.69 (s, 1H), 6.12 (s, 1H), 5.91 (s, 2H), 5.02 (ABq, 2H), 4.70 (ABq,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 167.9, 155.9, 148.9, 142.2,141.8, 134.7 (q, ¹J_(CF)=135 Hz), 132.1, 129.5, 124.5, 123.9, 123.8 (m),119.9, 109.2, 103.2, 101.9, 93.9, 80.2, 57.8, 40.9; MS (ES+) m/z 462.1(M+1).

EXAMPLE 4.83 Synthesis of6-fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-bromomethyl-2-(trifluoromethyl)furan toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and6-fluoro-5-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,6-fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (43%) as a colorless solid: mp 132-134° C.; ¹H NMR (300MHz, CDCl₃) δ7.58 (d, J=9.4 Hz, 1H), 7.27 (dd, J=7.7, 7.7 Hz, 1H),7.06-7.01 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.71-6.67 (m, 2H), 6.62 (d,J=12.1 Hz, 1H), 6.34 (d, J=3.4 Hz, 1H), 6.10 (d, J=3.4 Hz, 1H), 4.90 (d,J=16.3 Hz, 1H), 4.57 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.7 Hz, 1H), 4.41(d, J=16.2 Hz, 1H), 3.91 (s, 3H); MS (ES+) m/z 433.9 (M+1).

EXAMPLE 4.84 Synthesis of4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using chloroacetonitrile to replace2-(bromomethyl)tetrahydro-2H-pyran, and4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetonitrilewas obtained (94%) as a colorless solid: mp 122-123° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.41 (dd, J=8.0, 8.0 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H),7.11 (d, J=8.1 Hz, 1H), 6.62 (s, 1H), 6.29 (s, 1H), 5.90 (d, J=1.9 Hz,2H), 4.95 (ABq, 2H), 4.79 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.4,156.7, 149.2, 143.0, 141.9, 131.1, 130.4, 128.4, 124.6, 116.8, 115.8,108.8, 103.3, 101.9, 93.4, 77.6, 58.3, 29.2; MS (ES+) m/z 355.2 (M+1).

EXAMPLE 4.85 Synthesis of1′-[(2-amino-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-amino-(5-chloromethyl)thiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[(2-amino-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (73%) as a yellow solid: mp 230-235° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H),7.04-6.96 (m, 2H), 6.93 (s, 2H), 6.65 (s, 1H), 6.37 (s, 1H), 6.22 (s,1H), 5.89 (s, 2H), 4.76 (d, J=9.3 Hz, 1H), 4.67-4.59 (m, 3H); ¹³C NMR(75 MHz, DMSO-d₆) δ177.6, 166.8, 155.9, 148.9, 146.8, 143.9, 142.3,131.8, 129.6, 129.6, 124.3, 120.3, 109.9, 109.8, 103.1, 101.9, 93.9,80.4, 57.8, 14.8; MS (ES+) m/z 394.3 (M+1).

EXAMPLE 4.86 Synthesis of4′-bromo-1′-[1(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-chloro-5-(chloromethyl)thiophene toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,4′-bromo-1′-[1(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 85-87° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.19-7.11 (m, 2H), 6.88-6.85 (m, 2H), 6.76 (d, J=3.8 Hz, 1H),6.47 (s, 1H), 6.06 (s, 1H), 5.87 (d, J=5.8 Hz, 2H), 4.97 (ABq, 2H), 4.91(d, J=9.2 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.9, 157.2, 156.9,149.3, 143.3, 142.1, 136.3, 130.3, 129.8, 127.7, 126.3, 126.0, 120.2,116.1, 107.9, 102.6, 101.6, 93.3, 77.2, 59.5, 39.4; MS (ES+) m/z 490.3(M+1), 488.2 (M+1).

EXAMPLE 4.87 Synthesis of1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-chloro-5-(chloromethyl)thiophene toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2′-oxo-1,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrileto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrilewas obtained (78%) as a colorless solid: mp 192-193° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (dd, J=8.0, 1.1 Hz, 1H), 7.54 (dd,J=7.4, 1.1 Hz, 1H), 7.21 (dd, J=7.7, 7.7 Hz, 1H), 7.03 (s, 2H), 6.73 (s,1H), 6.35 (s, 1H), 5.95 (dd, J=4.0, 0.7 Hz, 2H), 5.29 (d, J=1.5 Hz, 2H),4.78 (dd, J=20.4, 9.6 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.0, 155.5,148.7, 143.2, 141.8, 137.6, 133.6, 133.2, 128.8, 127.9, 126.6, 126.5,123.7, 118.5, 116.9, 103.0, 101.5, 93.4, 92.6, 79.5, 56.4, 40.0; MS(ES+) m/z 437.3 (M+1), 439.3 (M+1).

EXAMPLE 4.88 Synthesis of1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)-2-isopropylthiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2′-oxo-1,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrileto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrilewas obtained (74%) as a colorless solid: mp=162-163° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 7.66 (dd, J=8.0, 1.2 Hz,1H), 7.52 (dd, J=7.4, 1.2 Hz, 1H), 7.39 (s, 1H), 7.19 (dd, J=7.7, 7.7Hz, 1H), 6.72 (s, 1H), 6.42 (s, 1H), 5.94 (s, 2H), 5.25 (ABq, 2H), 4.80(ABq, 2H), 3.28-3.15 (m, 1H), 1.26 (d, J=6.9 Hz, 6H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.5, 176.9, 155.4, 149.7, 148.6, 144.0, 141.8, 133.8,133.1, 128.4, 123.4, 119.0, 116.5, 114.3, 103.1, 101.5, 93.3, 93.1,79.4, 56.5, 40.9, 32.4, 22.7; MS (ES+) m/z 446.2 (M+1).

EXAMPLE 4.89 Synthesis of4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-chloro-5-(chloromethyl)thiophene toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 167-168° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 7.36 (dd, J=8.0, 8.0 Hz,1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=8.0, 0.7 Hz, 1H), 6.77 (d, J=3.4 Hz,1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d,J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.1, 156.2, 148.5, 143.3, 141.5, 137.5, 130.5, 129.8, 127.8, 127.7,127.3, 126.5, 123.6, 116.5, 108.3, 102.4, 101.4, 92.9, 77.0, 57.8, 38.7;MS (ES+) m/z 446.2 (M+1), 448.2 (M+1).

EXAMPLE 4.90 Synthesis of4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-bromomethyl-5-(trifluoromethyl)furan toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (43%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=0.7 Hz, 8.0Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s,2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); ¹³CNMR (75 MHz, DMSO-d₆) δ 176.1, 156.1, 152.7, 148.6, 143.4, 141.5, 139.5(q, ²J_(CF)=42 Hz), 130.5, 129.7, 127.9, 123.6, 118.8 (q, ¹J_(CF)=267Hz), 116.6, 114.0 (d, ³J_(CF)=3 Hz), 109.9, 108.2, 102.2, 101.4, 92.9,76.9, 57.9, 36.7; MS (ES+) m/z 464.3 (M+1), 466.3 (M+1).

EXAMPLE 4.91 Synthesis of4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)-2-isopropylthiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (62%) as a colorless solid: mp 147-148° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 7.47 (s, 1H), 7.31 (dd,J=8.0, 8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.65 (s, 1H), 6.33 (s, 1H),5.94 (s, 2H), 5.09 (d, J=16 Hz, 1H), 4.93 (d, J=9.7 Hz, 1H), 4.91 (d,J=16 Hz, 1H), 4.76 (d, J=9.7 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.5,176.1, 156.1, 149.5, 148.5, 144.1, 141.4, 130.3, 129.6, 128.1, 123.2,116.9, 115.2, 108.5, 102.7, 101.4, 92.8, 76.9, 57.9, 40.2, 32.4, 22.7,22.6; MS (ES+) m/z 455.3 (M+1), 457.3 (M+1).

EXAMPLE 4.92 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)-2-isopropylthiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: mp 164-165° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ7.58 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.32(dd, J=7.8, 7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.82-6.76 (m, 2H),6.42-6.37 (m, 3H), 5.96 (d, J=19.0 Hz, 2H), 5.11 (d, J=16.0 Hz, 1H),4.89 (d, J=16.0 Hz, 1H), 4.57 (d, J=9.4 Hz, 1H), 4.42 (d, J=9.4 Hz, 1H),3.29-3.20 (m, 1H), 2.99 (s, 6H), 1.31 (d, J=6.9 Hz, 6H); ¹³C NMR (75MHz, DMSO-d₆) δ 177.5, 176.9, 157.9, 155.4, 149.9, 148.3, 146.6, 142.6,141.5, 136.8 (2C), 129.2, 128.8, 125.2, 121.7, 121.1, 115.3, 108.6,104.3, 102.6, 101.3, 93.2, 77.2, 57.8, 37.6, 32.4, 22.8, 22.7; MS (ES+)m/z 541.3 (M+1).

EXAMPLE 4.93 Synthesis of3′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1-inden]-2′(3′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 1-(bromomethyl)-2-(fluoromethyl)benzene(Kirmse, W. et al. J. Org. Chem. (1994), 59(14):3821-3829) to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,3′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-onewas obtained (53%) as a colorless solid: mp 188-190° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.50 (d, J=6.6 Hz, 1H), 7.39-7.35 (m, 2H), 7.27-7.15 (m,3H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.54 (s, 1H),6.23 (s, 1H), 5.69-5.60 (m, 2H), 5.10-4.98 (m, 2H), 4.76 (ABq, 2H),4.20-4.11 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.3, 155.3, 144.7,142.8, 138.3, 135.3 (d, J_(C-F)=2.8 Hz), 134.2 (d, J_(C-F)=15.5 Hz),132.1, 130.4 (d, J_(C-F)=7.1 Hz), 130.0 (d, J_(C-F)=3.3 Hz), 129.3,128.1, 126.9 (d, J_(C-F)=1.8 Hz), 124.2, 123.6, 121.5, 111.7, 109.9,99.3, 82.9 (d, J_(C-F)=160.6 Hz), 80.1, 64.7, 64.1, 57.8, 55.4; MS (ES+)m/z 439.9 (M+23).

EXAMPLE 4.94 Synthesis of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using α-bromo-m-tolunitrile to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrilewas obtained (66%) as a colorless solid: mp 173-178° C. (ethylacetate/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.63 (m, 3H),7.44-7.47 (m, 1H), 7.21-7.24 (m, 2H), 7.05 (t, J=7.5 Hz, 1H), 6.72 (d,J=7.5 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.93-4.97 (m, 3H), 4.66-4.69(m, 1H), 4.13-4.17 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7, 155.3,144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 131.7, 130.9, 129.9, 129.0,124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9,58.0, 43.4; MS (ES+) m/z 410.8 (M+1).

EXAMPLE 4.95 Synthesis of1-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)-1-fluoro-2-methoxybenzeneto replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 161-163° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ 7.23-7.15 (m, 2H), 7.05-7.00 (m, 2H), 6.94-6.77(m, 3H), 6.49 (s, 1H), 6.18 (s, 1H), 5.09-5.04 (m, 1H), 4.97-4.91 (m,1H), 4.71-4.61 (m, 2H), 4.19-4.08 (m, 4H), 3.83 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 177.6, 155.2, 153.6, 150.4, 148.1, 144.7, 141.9, 138.3,132.2, 128.8, 124.0, 123.6, 121.0, 119.8, 116.1, 112.4, 111.3, 109.2,99.5, 79.9, 64.5, 63.9, 58.0, 56.2, 43.8; MS (ES+) m/z 433.8 (M+1).

EXAMPLE 4.96 Synthesis of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(bromomethyl)benzonitrile to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrilewas obtained (85%) as a colorless solid: mp 69-72° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.58 (m, 2H), 7.49-7.39(m, 2H), 7.23-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.69 (d, J=7.8 Hz, 1H),6.50 (s, 1H), 6.18 (s, 1H), 5.10 (d, J=16.1 Hz, 1H), 4.92 (d, J=9.0 Hz,1H), 4.85 (d, J=16.1 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H);MS (ES+) m/z 410.9 (M+1).

EXAMPLE 4.97 Synthesis of1′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(4-(bromomethyl)phenyl)isoxazole (0.20g, 0.84 mmol) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 209-212° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.28-8.25 (m, 1H), 7.77 (d,J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.23-7.13 (m, 2H), 7.02 (dd,J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.52-6.47 (m, 2H), 6.22 (s,1H), 5.11 (d, J=15.8 Hz, 1H), 4.94 (d, J=8.9 Hz, 1H), 4.84 (d, J=15.8Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.22-4.08 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ177.6, 168.8, 155.3, 150.9, 144.7, 141.9, 138.4, 138.0, 132.2,128.9, 128.0, 126.9, 126.5, 126.2, 124.1, 123.6, 120.9, 111.5, 109.2,99.5, 98.9, 80.2, 64.5, 64.0, 58.1, 43.9, 29.7; MS (ES+) m/z 453.0(M+1).

EXAMPLE 4.98 Synthesis of1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-chloromethyl-2-(trifluoromethyl)pyridineto replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (90%) as a colorless solid: mp 204-207° C.(dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 8.74 (d, J=1.6 Hz, 1H),7.82 (dd, J=8.1, 1.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 1H),7.03-7.05 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H),5.11 (d, J=16.0 Hz, 1H), 4.92 (d, J=16.1 Hz, 1H), 4.91 (d, J=9.0 Hz,1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.07 (m, 1H); ¹³C NMR (75 MHz, CDCl₃)δ 177.7, 155.3, 149.0, 147.9 (q, J=139.5 Hz), 144.8, 141.2, 138.4,136.5, 134.9, 132.1, 129.1, 124.4, 124.1, 121.4, 120.8 (q, J=10.8 Hz),120.5, 111.4, 108.6, 99.6, 80.1, 64.5, 63.9, 58.0, 41.3; MS (ES+) m/z429.9 (M+1).

EXAMPLE 4.99 Synthesis of1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(4-(bromomethyl)phenyl)isoxazole (0.20g, 0.84 mmol) to replace 2-(bromomethyl)tetrahydro-2H-pyran, and3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (60%) as a colorless solid: mp 192-194° C.; ¹H NMR (300MHz, DMSO-d₆) δ 8.25 (d, J=1.8 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.55 (d,J=8.2 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.27-7.09 (m, 2H), 7.02-6.95 (m,2H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 5.32 (d, J=16.2 Hz,1H), 5.15 (d, J=9.1 Hz, 1H), 4.89 (d, J=9.1 Hz, 1H), 4.83 (d, J=16.2 Hz,1H), 2.45 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 169.0, 164.0,158.2, 155.0, 150.8, 141.9, 137.4, 130.5, 129.4, 127.8, 126.8, 123.8,123.7, 123.1, 118.0, 109.7, 108.9, 108.0, 98.9, 81.4, 56.4, 53.5, 44.1,9.8; MS (ES+) m/z 449.9 (M+1).

EXAMPLE 4.100 Synthesis of1-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(chloromethyl)-5-fluoropyridinehydrochloride (Cai, Z. et al. US 2007/0072831) to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (99%) as a colorless solid: mp 174-176° C.; ¹H NMR (300MHz, CDCl₃) δ 8.40 (d, J=2.7 Hz, 1H), 7.41-7.11 (m, 4H), 7.01 (t, J=7.4Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.25 (s, 1H), 5.16 (d,J=15.7 Hz, 1H), 4.98-4.88 (m, 2H), 4.65 (d, J=8.9 Hz, 1H), 4.20-4.07 (m,4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 160.2, 157.2, 155.3, 151.5, 151.5,144.7, 142.0, 138.3, 137.8, 137.5, 132.2, 128.8, 124.1, 123.9, 123.8,123.6, 122.9, 122.8, 121.0, 111.6, 109.4, 99.4, 80.1, 64.5, 63.9, 58.1,45.4; MS (ES+) m/z 404.9 (M+1).

EXAMPLE 4.101 Synthesis of1-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(chloromethyl)-3-fluoropyridinehydrochloride (Weidmann, K. et al., J. Med. Chem. (1992), (35):438) toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (25%) as a colorless solid: mp 247-249° C.(dichloromethane/ether); ¹H NMR (300 MHz, CDCl₃) δ 8.35 (td, J=4.6, 1.34Hz, 1H), 7.43-7.33 (m, 1H), 7.27-7.11 (m, 3H), 7.02-6.95 (m, 1H),6.80-6.75 (m, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 5.31 (dd, J=16.2, 1.5 Hz,1H), 5.04 (dd, J=16.2, 1.4 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d,J=8.9 Hz, 1H), 4.20-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5,159.6, 156.2, 155.2, 145.4, 145.3, 144.5, 142.9, 142.8, 142.2, 138.3,132.6, 128.6, 124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2,80.2, 64.5, 63.9, 58.1, 40.7; MS (ES+) m/z 404.7 (M+1).

EXAMPLE 4.102 Synthesis of1-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: mp 228-230° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 10.70 (s, 1H), 7.42-7.32 (m,2H), 7.26 (t, J=7.8 Hz, 1H), 7.13-7.05 (m, 1H), 6.96-6.90 (m, 3H),6.79-6.70 (m, 5H), 6.23 (s, 1H), 6.12 (s, 1H), 4.47 (d, J=9.3 Hz, 1H),4.32 (d, J=9.3 Hz, 1H), 4.15-4.01 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.4, 150.3, 149.6, 147.2, 144.8, 142.7, 138.2, 137.2, 136.4,135.7, 131.2, 130.4, 129.2, 128.0, 126.9, 125.9, 122.9, 122.7, 121.8,111.3, 109.5, 99.6, 64.6, 64.1, 46.3; MS (ES+) m/z 513.9 (M+1).

EXAMPLE 4.103 Synthesis of4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (90%) as a colorless solid: mp 196-199° C.(dichloromethane/ether); ¹H NMR (300 MHz, CDCl₃) δ 8.61-8.57 (m, 1H),7.69-7.65 (m, 1H), 7.40-7.18 (m, 5H), 7.12-7.05 (m, 1H), 7.02-6.97 (m,2H), 6.93-6.86 (m, 2H), 6.84-6.71 (m, 4H), 6.39 (s, 1H), 6.21 (s, 1H),5.26 (d, J=15.8 Hz, 1H), 4.95 (d, J=15.8 Hz, 1H), 4.73 (d, J=9.0 Hz,1H), 4.43 (d, J=9.0 Hz, 1H), 4.20-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)δ 178.2, 157.4, 156.3, 155.6, 149.6, 144.7, 142.4, 139.8, 137.9, 137.1,133.5, 130.4, 130.1, 129.7, 128.7, 125.4, 123.1, 122.8, 122.3, 121.7,118.6, 118.4, 111.2, 108.7, 99.3, 77.9, 64.5, 64.0, 58.5, 46.2; MS (ES+)m/z 555.0 (M+1).

EXAMPLE 4.104 Synthesis of1-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(chloromethyl)-3,5-difluoropyridinehydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (64%) as a colorless solid: mp 220-222° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.27 (d, J=1.7 Hz, 1H),7.26-7.11 (m, 3H), 7.04-6.96 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.49-6.46(m, 1H), 6.39-6.36 (m, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.00 (d, J=16.1 Hz,1H), 4.95-4.90 (m, 1H), 4.68-4.63 (m, 1H), 4.20-4.06 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 177.5, 159.7, 156.2, 155.3, 144.6, 142.0, 139.0,138.9, 138.3, 133.8, 133.6, 132.5, 123.9, 123.4, 121.2, 112.0, 111.6,108.9, 99.2, 80.1, 64.5, 63.9, 58.1, 40.3; MS (ES+) m/z 422.8 (M+1).

EXAMPLE 4.105 Synthesis of2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrilewas obtained (89%) as a colorless solid: mp 151-153° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.55 (d, J=3.9 Hz, 1H), 7.66(t, J=7.5 Hz, 1H), 7.34-6.84 (m, 9H), 5.19 (d, J=15.8 Hz, 1H), 5.07 (d,J=9.2 Hz, 1H), 4.97 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H); ¹³C NMR(75 MHz, CDCl₃) δ 176.3, 160.7, 155.1, 149.7, 142.3, 137.1, 134.8,131.2, 129.5, 125.8, 124.6, 123.8, 122.9, 121.8, 118.5, 113.8, 113.3,109.9, 80.21, 77.5, 57.9, 46.1; MS (ES+) m/z 353.9 (M+1).

EXAMPLE 4.106 Synthesis of3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-(bromomethyl)benzonitrile to replace2-(bromomethyl)tetrahydro-2H-pyran, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrilewas obtained (75%) as a colorless solid: mp 94-96° C. (isopropylalcohol); ¹H NMR (300 MHz, CDCl₃) δ 7.65-7.52 (m, 4H), 7.49-7.42 (m,2H), 7.23-7.15 (m, 1H), 7.08-7.01 (m, 1H), 6.75-6.70 (m, 1H), 6.49 (s,1H), 6.18 (s, 1H), 5.03 (d, J=15.8 Hz, 1H), 4.95-4.84 (m, 2H), 4.66 (d,J=9.0 Hz, 1H), 4.20-4.07 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6,155.3, 144.8, 141.5, 138.4, 137.4, 132.1, 131.8, 130.9, 129.9, 129.0,124.3, 123.9, 120.7, 118.4, 113.1, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9,58.0, 43.4, 29.7; MS (ES+) m/z 411.0 (M+1). Anal. Calcd. for C₂₅H₁₈N₂O₄:C, 73.16; H, 4.42; N, 6.83. Found: C, 72.92; H, 5.05; N, 6.50.

EXAMPLE 4.107 Synthesis of(8S)-1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(chloromethyl)-2-fluoropyridinehydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,(8S)-1-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 210-212° C. (isopropylalcohol); ¹H NMR (300 MHz, CDCl₃)

8.40 (d, J=2.6 Hz, 1H), 7.41-7.11 (m, 4H), 7.05-6.97 (m, 1H), 6.89 (d,J=7.8 Hz, 1H), 6.49 (s, 1H), 6.25 (s, 1H), 5.16 (d, J=15.7 Hz, 1H),4.99-4.88 (m, 2H), 4.65 (d, J=8.9 Hz, 1H), 4.20-4.06 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 177.5, 160.6, 157.2, 155.3, 151.5, 144.7, 142.0,138.3, 137.8, 137.5, 132.2, 128.8, 124.1, 123.9, 123.8, 123.6, 122.9,121.0, 111.6, 109.4, 99.4, 80.1, 54.5, 63.9, 58.1, 45.4; MS (ES+) m/z404.9 (M+1). Anal. Calcd. for O₂₃H₁₇N₂O₄: C, 68.31; H, 4.24; N, 6.93.Found: C, 67.81; H, 4.39; N, 6.85.

EXAMPLE 4.108 and Example 4.109 Synthesis of(8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneand(S)-1′-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(chloromethyl)-3-fluoropyridinehydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,(8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (33%) as a colorless solid: mp 125-126° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

8.38-8.32 (m, 1H), 7.43-7.34 (m, 1H), 7.28-7.11 (m, 3H), 7.02-6.95 (m,1H), 6.78 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.31 (d, J=16.2Hz, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.95 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9Hz, 1H), 4.21-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 159.6,156.2, 155.2, 145.4, 144.5, 142.9, 142.8, 142.2, 138.3, 132.6, 128.6,124.3, 123.8, 123.3, 123.1, 121.3, 112.2, 109.0, 99.2, 80.2, 64.5, 63.9,58.1, 40.7; MS (ES+) m/z 404.9 (M+1). Anal. Calcd. for C₂₃H₁₇FN₂O₄: C,68.31; H, 4.24; N, 6.93. Found: C, 67.27; H, 4.24; N, 6.93.

(S)-1-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-onewas isolated (6%) as a byproduct from this reaction as a colorlesssolid: mp 182-183° C. (diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ7.28-7.20 (m, 1H), 7.17 (d, J=7.2 Hz, 1H), 7.07-7.00 (m, 1H), 6.63 (d,J=7.8 Hz, 1H), 6.47 (s, 1H), 6.37 (s, 1H), 4.89 (d, J=9.0 Hz, 1H),4.68-4.56 (m, 2H), 4.44 (d, J=17.9 Hz, 1H), 4.20-4.07 (m, 4H), 2.54 (q,J=7.3 Hz, 2H), 1.11 (t, J=7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 203.5,177.6, 155.2, 144.6, 141.9, 138.4, 132.2, 128.8, 124.0, 123.7, 120.9,111.9, 108.2, 99.3, 80.0, 64.5, 63.9, 58.0, 48.9, 33.2, 7.4; MS (ES+)m/z 366.0 (M+1).

EXAMPLE 4.110 Synthesis of1-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(chloromethyl)-4-fluoropyridinehydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless solid: mp 228-231° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

8.52 (dd, J=8.38, 5.56 Hz, 1H), 7.24-7.14 (m, 2H), 7.06-6.90 (m, 3H),6.85 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.15 (d, J=16.0 Hz,1H), 5.02-4.91 (m, 2H), 4.67 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H); ¹³CNMR (75 MHz, CDCl₃) δ 177.6, 171.0, 167.6, 158.9 (2), 155.3, 152.0 (2),144.7, 141.9, 138.4, 132.2, 128.9, 124.0, 123.7, 120.9, 111.7, 111.0,110.8, 109.7, 109.5, 109.3, 99.4, 80.1, 64.5, 63.9, 58.1, 45.8, 11.9; MS(ES+) m/z 404.9 (M+1).

EXAMPLE 4.111 Synthesis of1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using6-(chloromethyl)-2,3-dihydrobenzo[b][1,4]dioxine (Capilla, A. S. et al.,Tetrahedron (2001), 57:8297) to replace2-(bromomethyl)tetrahydro-2H-pyran, and2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrileto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrilewas obtained (54%) as a colorless solid: mp 181-183° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.29-7.16 (m,1H), 7.15-6.97 (m, 3H), 6.89-6.75 (m, 5H), 5.04 (d, J=9.2 Hz, 1H), 4.94(d, J=15.3 Hz, 1H), 4.80-4.67 (m, 2H), 4.25-4.19 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 176.2, 160.8, 143.8, 143.3, 142.2, 134.7, 131.3, 129.5,128.5, 125.8, 124.4, 123.8, 123.7, 120.5, 118.5, 117.8, 116.3, 113.8,113.3, 109.8, 80.2, 64.3 (2C), 57.8, 43.8.

EXAMPLE 4.112 Synthesis of1-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-chloro-2-(chloromethyl)pyridinehydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 176-178° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

8.35-8.31 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.27-7.15 (m, 3H), 7.09-7.02(m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (d, J=1.5 Hz, 1H), 6.23 (d, J=1.4Hz, 1H), 5.13 (d, J=16.8 Hz, 1H), 5.02-4.89 (m, 2H), 4.67 (dd, J=8.9,1.3 Hz, 1H), 4.22-4.06 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 155.4,150.0, 148.9, 144.8, 141.4, 138.4, 136.9, 132.0, 129.1, 129.8, 124.2,124.0, 123.0, 120.6, 111.4, 109.1, 99.6, 80.2, 64.5, 63.9, 58.1, 41.2.

EXAMPLE 4.113 Synthesis of1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using1-(chloromethyl)-2-(trifluoromethyl)benzene to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%) as a colorless solid: mp 207-208° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃)

7.72 (d, J=7.6 Hz, 1H), 7.51-7.42 (m, 2H), 7.42-7.34 (m, 3H), 7.22-7.12(m, 1H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31(s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.0 Hz, 1H), 4.97 (d,J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.24-4.09 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1,129.0, 128.3 (q, J=30.8 Hz), 127.7, 126.8, 126.4 (q, J=5.8 Hz), 124.4(q, J=273.7 Hz), 124.1, 123.8, 120.8, 111.5, 109.2, 99.5, 80.3, 64.5,63.9, 58.2, 40.6; MS (ES+) m/z 454.1 (M+1).

EXAMPLE 4.114 Synthesis of(8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 1-(bromomethyl)-2-(trifluoromethyl)benzeneto replace 2-(bromomethyl)tetrahydro-2H-pyran, and(8R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,(8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (87%) as a colorless solid: mp 137-138° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

7.72 (d, J=7.6 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.13 (m, 3H), 7.07-7.00(m, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d,J=17.1 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70(d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9,155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q,²J_(C-F)=30.8 Hz), 127.6, 126.8, 126.4 (q, ⁵J_(C-F)=5.8 Hz), 124.4 (q,¹J_(C-F)=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5,64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1). Anal. Calcd.for C₂₆H₁₈F₃NO₄: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.16; H, 4.11;N, 3.07.

EXAMPLE 4.115 Synthesis of5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace2-(bromomethyl)tetrahydro-2H-pyran, and5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,(5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (62%) as a colorless solid: mp 137-139° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, J=4.6 Hz, 1H), 8.22 (d, J=7.5 Hz,1H), 7.57-7.50 (m, 1H), 7.02-6.94 (m, 2H), 6.72 (d, J=7.9 Hz, 1H), 6.47(s, 1H), 6.40 (s, 1H), 5.29-5.03 (ABq, 2H), 4.76-4.64 (ABq, 2H),4.18-4.06 (m, 4H), 2.18 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.4,155.0, 153.0, 152.9, 144.5, 140.9, 138.2, 135.5 (q, ⁴J=5.31 Hz), 132.5,132.5, 129.3, 124.5, 124.4 (q, ¹J=273.6 Hz), 123.5 (q, 2J=32.3 Hz),123.5, 122.2, 112.3, 109.3, 99.1, 79.7, 64.7, 64.1, 57.8, 42.4 (q, J=3.1Hz), 21.0; MS (ES+) m/z 469.0 (M+1).

EXAMPLE 4.116 Synthesis of(8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(trifluoromethyl)benzyl bromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,(8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 137-138° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J=7.7 Hz, 1H), 7.52-7.33 (m, 2H),7.22-7.12 (m, 3H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s,1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.1 Hz, 1H),4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); ¹³CNMR (75 MHz, CDCl₃) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5,132.1, 129.0, 127.9 (q, ²J_(C-F)=30.8 Hz), 127.6, 126.8, 126.4 (q,⁵J_(C-F)=5.8 Hz), 124.4 (q, ¹J_(C-F)=273.8 Hz), 124.1, 123.8, 120.8,111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+)m/z 454.0 (M+1); Anal. Calcd. for C₂₅H₁₈F₃NO₄: C, 66.22; H, 4.00; N,3.09. Found: C, 66.06; H, 3.98; N, 3.12.

EXAMPLE 4.117 Synthesis of4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (75%) as a colorless solid: MS (ES+) m/z 465.7 (M+1), 466.7(M+1).

EXAMPLE 4.118 Synthesis of1′-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(bromomethyl)-2,1,3-benzothiadiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,t-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: mp 189-191° C.; ¹H NMR (300MHz, CDCl₃) δ8.04-7.90 (m, 2H), 7.63-7.55 (m, 1H), 7.22-7.15 (m, 2H),7.08-7.00 (m, 1H), 6.86-6.79 (m, 1H), 6.53 (s, 1H), 6.26 (s, 1H), 5.22(d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H),4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H); MS (ES+) m/z 443.8 (M+1).

EXAMPLE 4.119 Synthesis of1-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)-1,3-benzothiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (77%) as a colorless solid: mp 164-166° C.; ¹H NMR (300MHz, CDCl₃) δ8.04 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.54-7.46(m, 1H), 7.43-7.35 (m, 1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz,1H), 6.97 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.53 (d, J=16.2Hz, 1H), 5.24 (d, J=16.2 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0Hz, 1H), 4.24-4.11 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 165.9,155.3, 152.9, 144.7, 141.2, 138.3, 135.3, 132.1, 128.9, 126.3, 125.5,124.0, 123.9, 123.2, 121.9, 120.8, 111.8, 109.2, 99.4, 64.5, 63.9, 58.0,42.6; MS (ES+) m/z 442.8 (M+1).

EXAMPLE 4.120 Synthesis of1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)-1-methyl-1H-benzoimidazoleto replace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (20%) as a colorless solid: mp>240° C.; ¹H NMR (300 MHz,CDCl₃) δ7.58-7.53 (m, 2H), 7.30-7.14 (m, 5H), 7.06-6.99 (m, 1H), 6.60(s, 1H), 6.51 (s, 1H), 5.28 (ABq, 2H), 4.81 (d, J=9.3 Hz, 1H), 4.71 (d,J=9.3 Hz, 1H), 4.22-4.10 (m, 4H), 3.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃)δ 176.6, 154.5, 149.1, 144.1, 142.3, 141.7, 137.8, 136.1, 131.9, 128.5,123.3, 123.0, 122.1, 121.5, 121.4, 118.6, 112.0, 110.1, 109.7, 98.5,79.3, 64.1, 63.6, 57.3, 37.1, 29.8; MS (ES+) m/z 440.0 (M+1).

EXAMPLE 4.121 Synthesis of1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 4-(chloromethyl)-2-isopropylthiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 60-63° C.; ¹H NMR (300 MHz,CDCl₃) δ7.28-7.21 (m, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06-6.98 (m, 2H),6.92 (s, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 5.15 (d, J=16.2 Hz, 1H), 4.95(d, J=16.2 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H),4.22-4.08 (m, 4H), 3.37-3.22 (m, 1H), 1.39 (d, J=6.9 Hz, 6H); ¹³C NMR(75 MHz, CDCl₃) δ 178.5, 177.2, 155.2, 150.2, 144.6, 142.1, 138.3,132.2, 128.8, 123.7, 123.4, 121.1, 114.1, 111.6, 109.7, 99.4, 80.1,64.5, 63.9, 58.1, 40.6, 33.3, 23.1; MS (ES+) m/z 434.9 (M+1).

EXAMPLE 4.122 Synthesis of1-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 5-(bromomethyl)-2,1,3-benzooxadiazole toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp 164-166° C.; ¹H NMR (300MHz, CDCl₃) δ7.86 (d, J=9.3 Hz, 1H), 7.75 (s, 1H), 7.43-7.37 (m, 1H),7.25-7.19 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),6.53 (s, 1H), 6.23 (s, 1H), 5.13 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz,1H), 4.94 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.7, 155.3, 149.0, 148.7, 144.8, 141.4,139.7, 138.4, 132.0, 131.4, 129.0, 124.3, 124.0, 120.6, 117.8, 113.9,111.4, 108.8, 99.6, 80.1, 64.5, 63.9, 58.0, 44.0; MS (ES+) m/z 427.9(M+1).

EXAMPLE 4.123 Synthesis of tert-butyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,tert-butyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylatewas obtained (99%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.34-7.26 (m, 1H), 7.14-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.88 (d, J=7.8Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.62 (d,J=9.0 Hz, 1H), 4.23-4.06 (m, 6H), 3.80-3.44 (m, 2H), 2.76-2.59 (m, 2H),2.11-1.93 (m, 1H), 1.74-1.60 (m, 2H), 1.45 (s, 9H), 1.37-1.20 (m, 2H).

EXAMPLE 4.124 Synthesis of1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine to replace2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-onewas obtained (81%) as a colorless solid: mp 180-182° C.; ¹H NMR (300MHz, CDCl₃) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m,1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H),7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d,J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d,J=16.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ176.1, 163.0, 155.1, 149.4,148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9,121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).

EXAMPLE 4.125 Synthesis of1-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 3-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, andspiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: mp 230-232° C.; ¹H NMR (300MHz, CDCl₃) δ 8.74 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 7.88-7.82 (m, 2H),7.39-7.16 (m, 4H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H),5.35-5.24 (m, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.84 (d, J=15.9 Hz, 1H); ¹³CNMR (75 MHz, CDCl₃) δ176.1, 162.9, 149.4, 148.8, 148.3, 144.8, 141.7,135.1, 130.8, 129.8, 129.7, 123.9, 121.8, 119.4, 109.6, 106.9, 81.9,57.2, 42.0; MS (ES+) m/z 371.1 (M+1).

EXAMPLE 4.126 Synthesis of6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine to replace2-(bromomethyl)tetrahydro-2H-pyran, and6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,6-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-onewas obtained (81%) as a colorless solid: mp 197-199° C.; ¹H NMR (300MHz, CDCl₃) δ8.60 (d, J=2.1 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H),7.32 (d, J=7.5 Hz, 1H), 7.25-7.15 (m, 3H), 7.02 (dd, J=7.5, 7.5 Hz, 1H),6.83 (d, J=7.5 Hz, 1H), 6.79 (s, 1H), 5.35 (d, J=16.2 Hz, 1H), 5.00 (d,J=9.3 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.74 (d, J=9.0 Hz, 1H),4.16-3.86 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ175.9, 155.8, 151.7, 149.5,141.8, 138.6, 138.3, 136.7, 130.9, 128.9, 123.6, 123.4, 122.6, 121.4,118.2, 116.8, 109.4, 106.8, 81.7, 64.5, 63.8, 57.7, 46.3; MS (ES+) m/z421.2 (M+1), 423.2 (M+1).

EXAMPLE 4.127 Synthesis of1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine to replace2-(bromomethyl)tetrahydro-2H-pyran, and2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-onewas obtained (38%) as a colorless solid: mp 132-134° C.; ¹H NMR (300MHz, CDCl₃) δ8.60 (d, J=1.2 Hz, 1H), 7.60 (ddd, J=7.5, 7.5, 1.5 Hz, 1H),7.38-7.13 (m, 4H), 7.01 (dd, J=7.2, 7.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),6.74 (d, J=8.4 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 5.38 (d, J=16.2 Hz, 1H),4.96-4.83 (m, 2H), 4.65 (d, J=8.7 Hz, 1H), 4.17-3.86 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ176.6, 156.0, 155.9, 149.4, 141.7, 139.6, 138.0, 136.7,131.5, 128.6, 123.5, 123.2, 122.6, 121.4, 118.1, 115.7, 109.2, 102.4,81.4, 64.5, 63.8, 57.2, 46.2; MS (ES+) m/z 387.2 (M+1).

EXAMPLE 4.128 Synthesis of tert-butyl4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate to replace2-(bromomethyl)tetrahydro-2H-pyran, and5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,tert-butyl4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylatewas obtained (57%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.34(ddd, J=9.0, 7.6, 1.5 Hz, 1H), 7.16-7.06 (m, 2H), 6.92 (d, J=7.8 Hz,1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=10.3, 6.3 Hz, 1H), 4.95(d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.13 (br s, 2H), 3.74-3.56(m, 2H), 2.69 (t, J=12.4 Hz, 2H), 2.07-1.96 (m, 1H), 1.68-1.63 (m, 2H),1.45 (s, 9H), 1.32-1.26 (m, 2H); MS (ES+) m/z 493.3 (M+23).

EXAMPLE 4.129 Synthesis of1-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using (R)-(tetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran,and5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1′H)-onewas obtained (80%) as a colorless solid: mp 139-141° C.; ¹H NMR (300MHz, CDCl₃) δ 7.32-7.27 (m, 1H), 7.15-7.01 (m, 3H), 6.66 (s, 1H), 6.41(s, 1H), 4.88 (dd, J=8.9, 0.9 Hz, 1H), 4.63 (dd, J=8.9, 2.5 Hz, 1H),4.32-4.24 (m, 1H), 4.00-3.69 (m, 4H), 2.75-2.71 (m, 2H), 2.54 (br s,2H), 2.10-1.86 (m, 3H), 1.78-1.69 (m, 5H); ¹³C NMR (75 MHz, CDCl₃)δ178.0, 158.6, 142.9, 138.8, 132.4, 130.0, 128.6, 126.5, 123.6, 123.4,123.2, 110.1, 109.5 79.7, 76.9, 68.2, 57.9, 44.6, 29.9, 29.2, 29.0,25.6, 23.2, 23.0; MS (ES+) m/z 375.9 (M+1).

EXAMPLE 4.130 Synthesis of1-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 4 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)tetrahydro-2H-pyran, and7H-spiro[furo[2,3-g]quinoxaline-8,3′-indolin]-2′-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one,1′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-onewas obtained (93%) as a pale orange solid: mp 232-233° C.; ¹H NMR (300MHz, CDCl₃) δ8.64 (m, 1H), 8.59 (d, J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz,1H), 8.05 (d, J=9.3 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.77-7.67 (m, 1H),7.56 (d, J=9.0 Hz, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.96(t, J=7.5 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 5.56 (d, J=16.5 Hz, 1H), 5.25(d, J=9.0 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.91 (d, J=16.5 Hz, 1H); ¹³CNMR (75 MHz, CDCl₃) δ177.2, 162.5, 155.9, 149.4, 144.9, 142.3, 142.1,139.8, 139.8, 136.9, 132.6, 132.4, 128.8, 123.3, 123.2, 122.6, 121.9,121.4, 116.6, 109.6, 82.6, 57.7, 46.5; MS (ES+) m/z 381.2 (M+1).

EXAMPLE 5 Synthesis of1-[(2-methoxypyrimidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.28 g, 1.0 mmol) in dry N,N-dimethylformamide (6 mL) was added cesiumcarbonate (2.30 g, 7.1 mmol) at ambient temperature. The mixture wasstirred at ambient temperature for 30 min, and5-(chloromethyl)-2-methoxypyrimidine (0.34 g, 2.1 mmol) in dryN,N-dimethylformamide (3 mL) was added dropwise. The mixture was stirredat ambient temperature for 16 h, and additional cesium carbonate (0.68g, 2.1 mmol) and 5-(chloromethyl)-2-methoxypyrimidine (0.20 g, 1.3 mmol)were added. The mixture was stirred at ambient temperature for 64 h.Water (60 mL) was added and the mixture was extracted with ethyl acetate(3×60 mL). The combined organic solution was washed with brine (100 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo The residue was purified by column chromatography (hexanes/ethylacetate 1:1) to afford1-[(2-methoxypyrimidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.29 g, 73%) as a colorless solid: mp 203-204° C.; ¹H NMR (300 MHz,CDCl₃) δ8.57 (s, 2H), 7.30-7.23 (m, 1H), 7.22-7.17 (m, 1H), 7.11-7.04(m, 1H), 6.86-6.81 (m, 1H), 6.44-6.41 (m, 2H), 4.89 (ABq, 2H), 4.81(ABq, 2H), 4.59-4.50 (m, 2H), 4.01 (s, 3H), 3.10-2.90 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.9, 165.4, 161.9, 161.3, 158.8, 141.1, 132.7, 128.8,124.3, 123.9, 122.8, 120.1, 119.7, 118.7, 108.5, 93.3, 80.5, 72.4, 57.6,55.1, 38.8, 29.0; MS (ES+) m/z 402.1 (M+1).

EXAMPLE 5.1 Synthesis of7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations usingT-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace5-(chloromethyl)-2-methoxypyrimidine,7′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-onewas obtained (30%) as a colorless solid: mp 210-211° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ7.34-7.31 (m, 1H), 7.21-7.16 (m, 2H),7.10-7.05 (m, 1H), 6.67-6.65 (m, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.34(s, 2H), 4.85 (d, J=9.6 Hz, 1H), 4.74 (d, J=9.6 Hz, 1H), 4.57-4.48 (m,2H), 2.94 (t, J=3.0 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.4, 161.2,160.4, 154.1, 139.4, 138.9, 137.2, 135.4, 130.5, 124.6, 122.8, 120.6,120.1, 119.9, 118.7, 117.1, 114.3, 114.2, 108.7, 92.4, 79.8, 72.0, 56.6,28.1.

EXAMPLE 5.2 Synthesis of(3R)-1-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and1-bromo-3-methylbutane to replace 5-(chloromethyl)-2-methoxypyrimidine,(3R)-1-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (86%) as a colorless solid: mp 86-87° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.4 Hz, 1H),7.07-7.02 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.41 (s, 1H),4.92 (d, J=8.9 Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.52 (t, J=8.6 Hz, 2H),3.88-3.65 (m, 2H), 3.02-3.96 (m, 2H), 1.74-1.58 (m, 3H), 1.00 (d, J=6.3Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 161.7, 161.2, 142.3, 133.1,128.6, 123.8, 123.0, 120.3, 119.8, 118.7, 108.4, 93.1, 80.5, 72.3, 57.6,38.7, 36.1, 29.0, 26.0, 22.5, 22.4; MS (ES+) m/z 349.9 (M+1).

EXAMPLE 5.3 Synthesis of(3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and1-bromopentane to replace 5-(chloromethyl)-2-methoxypyrimidine,(3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (78%) as a colorless solid: mp 128-129° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.1 Hz, 1H),7.07-7.02 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.41 (s, 1H),4.92 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 8.64 (t, J=4.5 Hz, 2H),3.87-3.63 (m, 2H), 2.99 (t, J=4.5 Hz, 2H), 1.79-1.69 (m, 2H), 1.40-1.35(m, 4H), 0.94-0.89 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 161.6,161.2, 142.4, 133.0, 128.6, 123.8, 123.0, 120.3, 119.7, 118.7, 108.4,93.1, 80.5, 72.3, 57.6, 40.3, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 349.9(M+1).

EXAMPLE 5.4 Synthesis of(3R)-1-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(2-bromomethyl)pyridine hydrobromide to replace5-(chloromethyl)-2-methoxypyrimidine,(3R)-1-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether);1H NMR (300 MHz, DMSO-d₆) δ8.53-8.51 (m, 1H), 7.82-7.77 (m, 1H),7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.61 (s, 1H),6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.86 (d,J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t, J=8.7 Hz, 2H), 2.98 (t,J=8.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.0, 161.0, 160.4, 155.2,149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8, 122.6, 121.5, 120.6,119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7, 28.2; MS (ES+) m/z371.0 (M+1).

EXAMPLE 5.5 Synthesis of(3R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace5-(chloromethyl)-2-methoxypyrimidine,(3R)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: mp 68-70° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ7.32-7.26 (m, 1H), 7.20 (d, J=7.4 Hz, 1H),7.10-7.05 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.75-6.74 (m, 1H), 6.45 (s,1H), 6.42 (s, 2H), 5.12 (d, J=16.2 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.85(d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H),3.07-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.4, 161.8, 161.1, 151.9,141.9, 141.2, 132.5, 128.8, 123.9, 123.7, 120.5, 120.0 (2C), 118.7,112.6, 112.5, 109.2, 108.7, 93.1, 80.3, 72.3, 57.6, 36.8, 28.9; MS (ES+)m/z 427.9 (M+1).

EXAMPLE 5.6 Synthesis of(3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and(2-bromomethyl)pyridine hydrobromide to replace5-(chloromethyl)-2-methoxypyrimidine,(3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether);mp 84-85° C. (diethyl ether); ¹H NMR (300 MHz, DMSO-d₆) δ8.53-8.51 (m,1H), 7.82-7.77 (m, 1H), 7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92(m, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d,J=16.4 Hz, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t,J=8.7 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₅) δ177.0,161.0, 160.4, 155.2, 149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8,122.6, 121.5, 120.6, 119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7,28.2; MS (ES+) m/z 371.0 (M+1).

EXAMPLE 5.7 Synthesis of(3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace5-(chloromethyl)-2-methoxypyrimidine,(3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: mp 64-65° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ 7.32-7.26 (m, 1H), 7.20 (d, J=7.4 Hz, 1H),7.10-7.05 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.75-6.74 (m, 1H), 6.45 (s,1H), 6.42 (s, 2H), 5.12 (d, J=16.2 Hz, 1H), 4.96 (d, J=9.0 Hz, 1H), 4.85(d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H),3.07-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.4, 161.8, 161.1, 151.9,141.9, 141.2, 132.5, 128.8, 123.9, 123.7, 120.5, 120.0 (2C), 118.7,112.6, 112.5, 109.2, 108.7, 93.1, 80.3, 72.3, 57.6, 36.8, 28.9; MS (ES+)m/z 427.9 (M+1).

EXAMPLE 5.8 Synthesis of3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dioneto replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-5-(trifluoromethyl)furan to replace5-(chloromethyl)-2-methoxypyrimidine,3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dionewas obtained (59%) as a colorless solid: mp 198-199° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ 7.37-7.30 (m, 1H), 7.23-7.18 (m, 3H),7.12-7.03 (m, 2H), 6.77 (s, 1H), 6.56 (s, 1H), 5.17-4.99 (m, 2H),4.91-4.75 (m, 2H), 3.31 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.2,156.8, 154.3, 152.9, 141.5, 136.1, 132.9, 131.4, 128.9, 123.6, 123.3,121.5, 114.0 (2C), 109.8, 109.2, 104.2, 92.4, 79.3, 57.2, 36.4, 28.1; MS(ES+) m/z 456.4 (M+1).

EXAMPLE 5.9 Synthesis of1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A heterogeneous mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.41 g, 1.4 mmol), cesium carbonate (1.1 g, 3.5 mmol),2-(chloromethyl)-6-(trifluoromethyl)pyridine (0.33 g, 1.7 mmol) andN,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16h. The mixture was diluted with water (100 mL) and ethyl acetate (100mL). The layers were separated and the aqueous layer was extracted withethyl acetate (2×70 mL). The combined organic layers was washed withbrine (100 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 25% to 35% gradient of ethyl acetate in hexanes toafford1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(0.44 g, 70%) as a colorless solid: mp 195-196° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.15-8.07 (m, 1H), 7.85-7.79 (m, 1H), 7.75-7.70 (m, 1H),7.28-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.97-6.91 (m, 1H), 6.52 (s, 1H),6.29 (s, 1H), 5.16 (ABq, J=42.6, 16.9 Hz, 2H), 4.75 (ABq, J=37.3, 9.3Hz, 2H), 4.22-4.08 (m, 4H); ¹³C NMR (300 MHz, DMSO-d₆) δ 176.8, 156.5,154.6, 146.0 (q, J_(C-F)=33.7 Hz), 144.1, 142.3, 139.4, 137.8, 131.7,128.6, 125.4, 123.5, 123.0, 121.4 (q, J_(C-F)=272.7 Hz), 121.1, 119.5(m), 111.4, 109.1, 98.6, 79.5, 64.1, 63.5, 57.2, 44.2; MS (ES+) m/z455.0 (M+1).

EXAMPLE 5.10 Synthesis of1′-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 3-(chloromethyl)-2-(trifluoromethyl)pyridine to replace2-(chloromethyl)-6-(trifluoromethyl)pyridine,1-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (63%) as a colorless solid: mp 219-220° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.70-8.65 (m, 1H), 7.77-7.66 (m, 2H), 7.33-7.21 (m, 2H),7.13-7.05 (m, 1H), 6.90-6.83 (m, 1H), 6.52 (s, 1H), 6.37 (s, 1H), 5.14(s, 2H), 4.78 (ABq, J=42.3, 9.4 Hz, 2H), 4.23-4.07 (m, 4H); ¹³C NMR (300MHz, DMSO-d₆) δ 177.0, 154.7, 147.9, 144.2, 143.4 (q, J_(C-F)=33.3 Hz),142.0, 137.8, 136.3, 131.7, 130.8, 128.9, 127.7, 123.8, 123.3, 122.1 (q,J_(C-F)=275.6 Hz), 120.9, 111.6, 109.0, 98.7, 79.6, 64.2, 63.5, 57.2,48.5; MS (ES+) m/z 455.0 (M+1).

EXAMPLE 5.11 Synthesis of1-{[3-(trifluoromethyl)pyrazin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 2-(bromomethyl)-3-(trifluoromethyl)pyrazine to replace2-(chloromethyl)-6-(trifluoromethyl)pyridine,1′-{[3-(trifluoromethyl)pyrazin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: mp 230-232° C.; ¹H NMR (300MHz, CDCl₃) δ8.69-8.66 (m, 1H), 8.60-8.57 (m, 1H), 7.23-7.15 (m, 2H),7.08-7.01 (m, 1H), 6.63-6.58 (m, 1H), 6.52 (s, 1H), 6.51 (s, 1H), 5.33(ABq, J=79.0, 17.6 Hz, 2H), 4.85 (ABq, J=75.4, 8.9 Hz, 2H), 4.23-4.11(m, 4H); ¹³C NMR (300 MHz, CDCl₃) δ 178.1, 155.1, 148.9, 146.8, 144.6,142.1, 141.8, 141.7 (q, J_(C-F)=36.1 Hz), 138.2, 132.6, 128.7, 124.0,123.6, 121.6 (q, J_(C-F) 273.4 Hz), 121.2, 112.2, 108.2, 99.2, 80.0,64.5, 63.9, 58.1, 41.2 (q, J_(C-F)=3.9 Hz); MS (ES+) m/z 455.9 (M+1).

EXAMPLE 5.12 Synthesis of1′-{[4-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 3-(chloromethyl)-4-(trifluoromethyl)pyridinehydrochloride to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine,1′-{[4-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (51%) as a colorless solid: mp 131-132° C.; ¹H NMR (300MHz, CDCl₃) δ8.78-8.72 (m, 1H), 8.51 (s, 1H), 7.64-7.60 (m, 1H),7.25-7.18 (m, 2H), 7.12-7.05 (m, 1H), 6.65-6.60 (m, 1H), 6.53 (s, 1H),6.32 (s, 1H), 5.32-5.11 (m, 2H), 4.84 (ABq, J=78.9, 8.9 Hz, 2H),4.24-4.10 (m, 4H); ¹³C NMR (300 MHz, CDCl₃) δ 177.9, 155.3, 149.9,148.9, 144.8, 141.3, 138.4, 135.8 (q, J_(C-F)=32.8 Hz), 132.0, 129.1,128.1, 124.3, 124.1, 123.0 (q, J_(C-F)=275.0 Hz), 120.4, 119.6 (m),111.6, 108.8, 99.5, 80.2, 64.5, 63.9, 58.1, 38.8 (m); MS (ES+) m/z 455.0(M+1).

EXAMPLE 5.13 Synthesis of1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 2-chloro-6-(chloromethyl)pyridine hydrochloride toreplace 3-(chloromethyl)-2-(trifluoromethyl)pyridine,1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (90%) as a colorless solid: mp 181-182° C.; ¹H NMR (300MHz, CDCl₃) δ7.67-7.59 (m, 1H), 7.28-7.22 (m, 2H), 7.22-7.13 (m, 2H),7.08-7.02 (m, 1H), 6.90-6.84 (m, 1H), 6.52 (s, 1H), 6.32 (s, 1H),5.23-5.14 (m, 1H), 4.98-4.89 (m, 2H), 4.70-4.65 (m, 1H), 4.24-4.09 (m,4H); ¹³C NMR (300 MHz, CDCl₃) δ 177.5, 156.4, 155.2, 151.2, 144.6,141.7, 139.7, 138.3, 132.1, 128.9, 123.9, 123.7, 123.4, 120.8, 119.9,111.6, 109.3, 99.4, 80.1, 64.5, 63.9, 58.1, 45.4; MS (ES+) m/z 420.7(M+1), 422.7 (M+1).

EXAMPLE 5.14 Synthesis of1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 5-(chloromethyl)-2-methoxypyrimidine hydrochloride toreplace 3-(chloromethyl)-2-(trifluoromethyl)pyridine,1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: mp 248-249° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.64 (s, 2H), 7.34-7.27 (m, 1H), 7.21-7.14 (m, 2H),7.08-7.01 (m, 1H), 6.51 (s, 1H), 6.10 (s, 1H), 4.98-4.85 (m, 2H), 4.73(ABq, J=49.9, 9.4 Hz, 2H), 4.21-4.06 (m, 4H), 3.89 (s, 3H); ¹³C NMR (300MHz, CDCl₃) δ 176.8, 164.6, 158.9, 154.6, 144.1, 141.6, 137.7, 131.8,128.7, 123.6, 123.5, 123.1, 121.0, 110.9, 109.2, 98.7, 79.3, 64.1, 63.5,57.1, 54.6, 38.0; MS (ES+) m/z 418.2 (M+1).

EXAMPLE 5.15 Synthesis of1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 5-(chloromethyl)-2-methoxypyridine hydrochloride toreplace 3-(chloromethyl)-2-(trifluoromethyl)pyridine,1-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (34%) as a colorless solid: mp 161-162° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.26-8.22 (m, 1H), 7.69-7.63 (m, 1H), 7.32-7.25 (m, 1H),7.19-7.08 (m, 2H), 7.07-7.00 (m, 1H), 6.84-6.79 (m, 1H), 6.52 (s, 1H),6.05 (s, 1H), 4.91-4.86 (m, 2H), 4.73 (ABq, J=42.8, 9.4 Hz, 2H),4.22-4.06 (m, 4H), 3.82 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.7,163.0, 154.6, 145.9, 144.1, 141.8, 138.5, 137.7, 131.7, 128.7, 125.0,123.6, 123.1, 121.1, 110.8, 110.7, 109.3, 98.8, 79.3, 64.1, 63.5, 57.2,53.1; MS (ES+) m/z 416.9 (M+1).

EXAMPLE 5.16 Synthesis of(8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 2-(chloromethyl)pyrazine to replace3-(chloromethyl)-2-(trifluoromethyl)pyridine, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-onewas obtained (62%) as a colorless solid: mp 216-218° C.; ¹H NMR (300MHz, CDCl₃) δ 8.65-8.62 (m, 1H), 8.58-8.50 (m, 2H), 7.27-7.15 (m, 2H),7.09-7.01 (m, 1H), 6.91-6.85 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.13(ABq, J=55.5, 16.1 Hz, 2H), 4.81 (ABq, J=81.0, 9.0 Hz, 2H), 4.24-4.09(m, 4H); ¹³C NMR (300 MHz, CDCl₃) δ177.5, 155.2, 151.2, 144.6, 144.2,143.9, 143.8, 141.7, 138.3, 132.2, 128.8, 124.0, 123.7, 120.8, 111.7,109.1, 99.4, 80.0, 64.5, 63.8, 58.0, 43.7; MS (ES+) m/z 387.8 (M+1);Anal. Calcd for C₂₂H₁₇N₃O₄: C, 68.21; H, 4.42; N, 10.85. Found: C,67.81; H, 4.39; N, 10.84.

EXAMPLE 5.17 Synthesis of(8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9 and makingnon-critical variations using 5-(chloromethyl)-2-methoxypyrimidinehydrochloride to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine,and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(8S)-1-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless solid: mp 102-104° C.; ¹H NMR (300MHz, CDCl₃) δ 8.56 (s, 2H), 7.30-7.22 (m, 1H), 7.21-7.15 (m, 1H),7.11-7.02 (m, 1H), 6.85-6.81 (m, 1H), 6.51 (s, 1H), 6.17 (s, 1H),4.98-4.77 (m, 3H), 4.66-4.61 (m, 1H), 4.24-4.09 (m, 4H), 4.00 (s, 3H);¹³C NMR (300 MHz, CDCl₃) δ 177.5, 165.4, 158.8, 155.2, 144.7, 141.2,138.4, 132.2, 128.9, 124.3, 123.9, 122.7, 120.5, 111.4, 108.5, 99.5,80.1, 64.5, 63.9, 57.9, 55.1, 38.9; MS (ES+) m/z 417.8 (M+1); Anal.Calcd for C₂₃H₁₉N₃O₅: C, 66.18; H, 4.59; N, 10.07. Found: C, 65.94; H,4.68; N, 9.77.

EXAMPLE 5.18 Synthesis of(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 5.9, making non-criticalvariations using 2-(chloromethyl)pyrimidine hydrochloride to replace3-(chloromethyl)-2-(trifluoromethyl)pyridine, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (59%) as a colorless solid: mp 210-212° C.; ¹H NMR (300MHz, CDCl₃) δ 8.72-8.68 (m, 2H), 7.23-7.14 (m, 3H), 7.06-6.99 (m, 1H),6.74-6.69 (m, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 5.21 (ABq, J=82.1, 17.0Hz, 2H), 4.86 (ABq, J=81.2, 8.9 Hz, 2H), 4.22-4.10 (m, 4H); ¹³C NMR (300MHz, CDCl₃) δ 177.8, 164.6, 157.5, 155.1, 144.5, 142.2, 138.2, 132.6,128.6, 123.8, 123.3, 121.5, 119.8, 112.3, 108.7, 99.1, 80.0, 64.5, 63.9,58.1, 45.7; MS (ES+) m/z 387.9 (M+1); Anal. Calcd for C₂₂H₁₇N₃O₄: C,68.21; H, 4.42; N, 10.85. Found: C, 68.17; H, 4.41; N, 10.76.

EXAMPLE 5.19 Synthesis of6-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione

To a stirred solution of6-methyl-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione(0.07 g, 0.21 mmol) in N,N-dimethylformamide (5 mL) was added cesiumcarbonate (0.20 g, 0.61 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 30 min, 2-(bromomethyl)pyridine hydrobromide (0.08 g, 0.31mmol) was added and the mixture was stirred at ambient temperature for18 h. The mixture was diluted with water and ethyl acetate. The organicphase was washed with water and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by column chromatography and eluted with ethylacetate/hexanes (3/2) to afford6-methyl-1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4-dioxino[2,3-f]indole-8,3′-indole]-2′,7(1H,6H)-dione(0.02 g, 26%): mp 87-89° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 8.64-8.63 (m, 1H), 7.71-7.62 (m, 2H), 7.26-7.17 (m, 2H),6.96-6.47 (m, 3H), 6.47 (s, 1H), 6.46 (s, 1H), 5.33 (s, 2H), 4.24-4.06(m, 4H), 3.22 (s, 3H); MS (ES+) m/z 414.0 (M+1).

EXAMPLE 5.20 Synthesis of4′-fluoro-1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.31 g, 1.00 mmol), 2-(chloromethyl)-3-(trifluoromethyl)pyridinehydrochloride (0.29 g, 1.50 mmol) and cesium carbonate (0.98 g, 3.00mmol) in N,N′ dimethylformamide (10 mL) was heated at 60° C. for 2 h andwas filtered while hot. The filtrate was allowed to cool to ambienttemperature and water was added, causing a precipitate to be deposited.The solid was collected by filtration, washed with water (50 mL) anddried under vacuum. The residue was recrystallized from N,N′dimethylformamide/water to afford4′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.39 g, 82%) as a beige solid: mp 245-247° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (d, J=4.5 Hz, 1H), 8.27 (d, J=7.65 Hz, 1H), 7.59 (dd,J=7.8, 4.9 Hz, 1H), 7.30 (ddd, J=8.2, 8.2, 5.8 Hz, 1H), 6.86 (d, J=9.0Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.54 (s, 1H), 6.49 (s, 1H), 5.25 (ABq,J=17.4 Hz, 2H), 4.79 (q, J=9.4 Hz, 2H), 4.22-4.10 (m, 4H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.5, 157.9 (d, ¹J_(C-F)=247 Hz), 154.6, 152.3, 152.1(d, ⁵J_(C-F)=1.2 Hz), 144.9 (d, ⁴J_(C-F)=8.9 Hz), 144.3, 137.6, 135.1(q, ⁴J_(C-F)=4.9 Hz), 130.8 (d, ⁴J_(C-F)=8.6 Hz), 125.6 (q, ¹J_(C-F)=274Hz), 123.0, 122.9 (d, ²J_(C-F)=32.3 Hz), 119.4, 117.1 (d, ³J_(C-F)=19.3Hz), 111.5, 109.9 (d, ³J_(C-F)=19.9 Hz), 105.7 (d, ⁵J_(C-F)=2.9 Hz),98.4, 77.4, 64.1, 63.5, 56.0 (d, ⁵J_(C-F)=1.7 Hz), 42.3 (q, ⁵J_(C-F)=3.3Hz); MS (ES+) m/z 460.9 (M+1).

EXAMPLE 5.21 Synthesis of1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.29 g, 1.00 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (0.21 g,1.20 mmol), cesium carbonate (0.65 g, 2.00 mmol) andN,N′-dimethylformamide (2.5 mL) was heated at 40° C. for 2 h andfiltered while hot. The filtrate was allowed to cool to ambienttemperature and water was added, causing a precipitate to be deposited.The solid was collected by filtration, washed with water and dried undervacuum. The residue was recrystallized from ethanol/diethyl ether toafford1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.28 g, 73%) as a colourless solid: mp 162-164° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.35 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 7.23 (dd, J=7.9 Hz, 1H),7.17 (d, J=6.9 Hz, 1H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.51 (d, J=1.9 Hz,1H), 6.13 (d, J=6.2 Hz, 1H), 4.71 (dd, J=9.3 Hz, 1H), 4.69 (dd, J=9.3Hz, 1H), 4.17 (dd, J=3.7 Hz, 2H), 4.10 (dd, J=3.4 Hz, 2H), 3.87 (d,J=6.9 Hz, 2H), 2.33-2.14 (m, 1H), 1.74-1.60 (m, 1H), 1.48-1.29 (m, 1H);¹³C NMR (75 MHz, DMSO-d₆) δ 176.5 (d, ⁴J_(C-F)=15.9 Hz), 154.5 (d,⁶J_(C-F)=1.4 Hz), 144.1 (d, ⁶J_(C-F)=1.9 Hz), 141.9, 137.7 (d,⁵J_(C-F)=3.9 Hz), 131.7 (d, ⁶J_(C-F)=2.3 Hz), 128.8, 123.5, 122.9 (d,⁶J_(C-F)=1.6 Hz), 121.2 (d, ⁵J_(C-F)=4.1 Hz), 114.3 (q, ¹J_(C-F)=283.4Hz), 110.9 (d, ²J_(C-F)=18.1 Hz), 109.1, 98.7 (d, ⁵J_(C-F)=3.6 Hz), 79.2(d, ⁵J_(C-F)=3.7 Hz), 64.1, 63.5, 57.1 (d, ⁶J_(C-F)=2.4 Hz), 36.6 (t,³J_(C-F)=5.9 Hz), 20.1 (t, ²J_(C-F)=17.4 Hz), 14.7 (t, ²J_(C-F)=10.7Hz); MS (ES+) m/z 386.2 (M+1).

EXAMPLE 5.22 Synthesis of1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.21 and makingnon-critical variations using dimethyl sulfate to replace2-(bromomethyl)-1,1-difluorocyclopropane,1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (28%) as a colourless solid: mp 152-154° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.34 (d, J=7.6 Hz, 1H), 7.15-7.01 (m, 3H), 6.50 (s, 1H),6.18 (s, 1H), 4.67 (d, J=9.3 Hz, 2H), 4.13 (dd, J=4.5, 2.8 Hz, 4H), 3.14(s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.9, 155.1, 144.5, 143.7, 138.2,132.2, 129.2, 123.7, 123.3, 121.7, 111.8, 109.3, 99.1, 79.9, 64.6, 64.0,57.6, 26.9; MS (ES+) m/z 310.2 (M+1).

EXAMPLE 5.23 Synthesis of1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.21 and makingnon-critical variations using2-(bromomethyl)-4-(trifluoromethyl)thiazole to replace2-(bromomethyl)-1,1-difluorocyclopropane,1′-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (58%) as a colourless solid: mp 169-170° C.; ¹H NMR (300MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.21 (d,J=6.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.08 (dd, J=7.3, 7.3 Hz, 1H),6.53 (s, 1H), 6.22 (s, 1H), 5.36 (ABq, J=16.9 Hz, 2H), 4.74 (dd, J=9.4Hz, 2H), 4.14 (dd, J=4.7, 3.1 Hz, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.5, 168.6, 154.5, 144.1, 143.3, 142.2 (d, ²J_(C-F)=36.5 Hz), 137.8,131.6, 128.8, 124.5 (q, ³J_(C-F)=6.6 Hz), 123.7, 123.4, 120.9, 120.3 (q,¹J_(C-F)=270 Hz), 111.1, 109.1, 98.7, 79.2, 64.1, 63.5, 57.1, 41.1; MS(ES+) m/z 460.9 (M+1).

EXAMPLE 5.24 Synthesis of(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetonitrile

Following the procedure as described in Example 5.9 and makingnon-critical variations using bromoacetonitrile to replace2-(chloromethyl)-6-(trifluoromethyl)pyridine,(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetonitrilewas obtained (54%) as a colorless solid: mp 161-162° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

7.35-7.38 (m, 1H), 7.23-7.10 (m, 2H), 7.04 (d, J=7.8 Hz, 1H), 6.48 (s,1H), 6.21 (s, 1H), 4.87 (d, J=9.1 Hz, 1H), 4.67 (d, J=3.7 Hz, 2H), 4.63(d, J=9.1 Hz, 1H), 4.20-4.05 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 176.6,155.2, 144.9, 139.7, 138.5, 131.6, 129.3, 124.8, 124.4, 120.1, 113.6,111.6, 108.7, 99.6, 79.9, 64.5, 63.9, 57.9, 28.0; MS (ES+) m/z 334.9(M+1).

EXAMPLE 5.25 Synthesis of9-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 50 mL round bottom flask was charged with9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.63 g, 2.0 mmol), 2-(bromomethyl)pyridine hydrobromide (0.51 g, 2.0mmol), cesium carbonate (3.26 g, 10.0 mmol) and N,N-dimethylformamide(20 mL). The reaction mixture was heated at 90° C. for 1 h, allowed tocool to ambient temperature, filtered and the filtrate concentrated invacuo. Purification of the residue by column chromatography and elutedwith a 0% to 70% gradient of ethyl acetate in dichloromethane afforded9-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.46 g, 57%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.45(d, J=4.3 Hz, 1H), 7.71-7.77 (m, 1H), 7.40-6.87 (m, 6H), 6.19 (d, J=1.8Hz, 1H), 5.02 (ABq, 2H), 4.84 (ABq, 2H), 4.27-4.09 (m, 4H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.7, 155.6, 149.6, 143.1, 142.1, 142.0, 139.2, 139.2,138.5, 137.5, 135.3, 133.9, 133.7, 131.5, 129.3, 124.1, 123.4, 123.2,122.7, 122.7, 122.1, 109.9, 106.6, 106.6, 80.8, 64.7, 64.1, 58.0, 58.0,45.2; MS (ES+) m/z 404.8 (M+1).

EXAMPLE 5.26 Synthesis of9-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations using2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace2-(bromomethyl)pyridine hydrobromide,9-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (25%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.62 (d, J=4.3 Hz, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.53 (dd, J=7.7, 5.0 Hz,1H), 7.28-6.83 (m, 4H), 6.29 (d, J=1.8 Hz, 1H), 5.20 (ABq, 2H), 4.84(ABq, 2H), 4.27-4.10 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.9, 152.8,143.4, 142.0, 141.9, 139.2, 139.2, 138.5, 135.5, 135.4, 135.4, 135.2,133.9, 133.7, 131.5, 129.3, 126.1, 124.1, 123.7, 123.4, 123.4, 123.2,122.8, 122.8, 122.5, 109.6, 106.8, 106.8, 80.6, 64.7, 64.1, 58.0, 58.0,42.4, 42.4; MS (ES+) m/z 472.9 (M+1).

EXAMPLE 5.27 Synthesis of9-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations using 5-(benzyloxy)-2-(chloromethyl)pyridinehydrochloride to replace 2-(bromomethyl)pyridine hydrobromide,1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(59%) was obtained as a colorless solid: MS (ES+) m/z 511.0 (M+1). Amixture of the1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onefrom the last step, palladium on carbon (10% w/w, 0.2 g), methanol (50mL) and acetic acid (1 drop) was hydrogenated at a pressure of 50 psi atambient temperature for 5 h. The reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography and eluted with a 0% to 70% gradient of ethyl acetate indichloromethane to afford9-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.37 g, 46%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ9.88 (s,1H), 8.00 (d, J=2.6 Hz, 1H), 7.25-7.09 (m, 4H), 7.01-6.87 (m, 2H), 6.12(d, J=1.8 Hz, 1H), 4.88 (ABq, 2H), 4.82 (ABq, 2H), 4.29-4.09 (m, 4H);¹³C NMR (75 MHz, DMSO-d₆) δ176.0, 152.8, 145.2, 142.6, 141.5, 141.4,138.7, 138.0, 137.1, 134.8, 133.4, 133.2, 131.0, 128.8, 123.5, 123.0,122.8, 122.4, 122.2, 109.5, 106.0, 80.2, 64.3, 63.6, 57.5, 44.2; MS(ES+) m/z 421.1 (M+1).

EXAMPLE 5.28 Synthesis of1′-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations using7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one toreplace9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-onewas obtained (87%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.46 (d, J=4.8 Hz, 1H), 7.71-7.77 (m, 1H), 7.37-6.88 (m, 6H), 6.64 (s,1H), 6.18 (s, 1H), 5.03 (ABq, 2H), 4.72 (ABq, 2H), 4.04-3.84 (m, 2H),2.66 (t, J=6.4 Hz, 2H), 1.88-1.67 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.1, 155.7, 154.3, 149.7, 149.4, 143.0, 137.5, 132.3, 129.1, 128.6,123.9, 123.6, 123.4, 123.1, 122.0, 111.5, 110.4, 109.8, 79.3, 66.2,58.0, 45.2, 25.2, 22.1; MS (ES+) m/z 384.8 (M+1).

EXAMPLE 5.29 Synthesis of1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations using7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one toreplace9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride toreplace 2-(bromomethyl)pyridine hydrobromide,1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H-spiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-onewas obtained (2%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.65(d, J=4.4 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.56 (dd, J=7.8, 5.0 Hz, 1H),7.20-7.26 (m, 1H), 7.15 (d, J=6.9 Hz, 1H), 7.01 (t, J=7.4 Hz, 1H), 6.88(d, J=7.8 Hz, 1H), 6.65 (s, 1H), 6.31 (s, 1H), 5.22 (ABq, J=39.2 Hz,2H), 4.72 (ABq, J=18.8 Hz, 2H), 4.04-3.95 (m, 2H), 2.70 (t, J=6.4 Hz,2H), 1.89-1.77 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.1, 155.7, 154.3,149.7, 149.4, 143.0, 137.5, 132.3, 129.1, 128.6, 123.9, 123.6, 123.4,123.1, 122.0, 111.5, 110.4, 109.8, 79.3, 66.2, 58.0, 45.2, 25.2, 22.1;MS (ES+) m/z 453.2 (M+1).

EXAMPLE 5.30 Synthesis of ethyl2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate

A 50 mL round-bottom flask was charged with2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(2.0 g, 6.8 mmol), ethyl 2-(bromomethyl)nicotinate (2.3 g, 9.4 mmol),cesium carbonate (6.62 g, 20.3 mmol), potassium iodide (0.17 g, 1.0mmol) and N,N-dimethylformamide (30 mL). The reaction mixture wasstirred under nitrogen at 95° C. for 1 h, allowed to cool to ambienttemperature and concentrated in vacuo. Purification of the residue bycolumn chromatography and eluted with a 0% to 30% gradient of ethylacetate in dichloromethane afforded ethyl2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate(2.4 g, 79%) as an off-white solid: MS (ES+) m/z 459.0 (M+1).

EXAMPLE 5.31 Synthesis of1-(pyridin-2-ylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one5,5′-dioxide

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations usingspiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one 5,5′-dioxide toreplace9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′1-1)-one,1-(pyridin-2-ylmethyl)spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1′H)-one5,5′-dioxide was obtained (43%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.44 (d, J=4.8 Hz, 1H), 7.87-6.91 (m, 11H), 5.11 (ABq, 2H),4.96 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 176.0, 165.5, 155.2, 149.4,143.0, 137.6, 134.3, 131.1, 129.9, 129.1, 128.6, 128.5, 126.4, 124.4,124.1, 123.8, 123.3, 122.9, 111.4, 110.4, 81.3, 56.4, 44.8; MS (ES+) m/z416.9 (M+1).

EXAMPLE 5.32 Synthesis of1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(chloromethyl)pyrimidine hydrochloride to replace5-(chloromethyl)-2-methoxypyrimidine,1-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (90%): mp 278-279° C.; ¹H NMR (300 MHz, CDCl₃) δ8.67 (d,J=4.9 Hz, 2H), 7.20-7.11 (m, 3H), 7.05-6.94 (m, 1H), 6.72-6.67 (m, 1H),6.54 (s, 1H), 6.47 (s, 1H), 5.19 (ABq, 2H), 4.83 (ABq, 2H), 4.21-4.02(m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 164.6, 157.5, 155.1, 144.5,142.2, 138.2, 132.6, 128.6, 123.8, 123.3, 121.5, 119.8, 112.3, 108.7,99.1, 80.0, 64.5, 63.9, 58.1, 45.7; MS (ES+) m/z 387.9 (M+1).

EXAMPLE 5.33 Synthesis of1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(chloromethyl)-4,6-dimethoxypyrimidine to replace5-(chloromethyl)-2-methoxypyrimidine,1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (90%): mp 169-170° C.; ¹H NMR (300 MHz, CDCl₃) δ7.21-7.11(m, 2H), 7.06-6.95 (m, 1H), 6.81-6.67 (m, 1H), 6.49 (s, 1H), 6.37 (s,1H), 5.89 (s, 1H), 4.98 (ABq, 2H), 4.80 (ABq, 2H), 4.23-4.00 (m, 4H),3.80 (s, 6H); MS (ES+) m/z 447.9 (M+1).

EXAMPLE 5.34 Synthesis of6-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace5-(chloromethyl)-2-methoxypyrimidine,6-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (72%): mp 94-95° C.; ¹H NMR (300 MHz, CDCl₃) δ8.56 (d,J=4.7 Hz, 1H), 7.69-7.59 (m, 1H), 7.25-7.09 (m, 4H), 7.05-6.95 (m, 1H),6.92-6.82 (m, 2H), 6.81-6.73 (m, 1H), 6.37 (s, 1H), 5.08 (ABq, 2H), 4.83(ABq, 2H), 3.93 (t, J=4.7 Hz, 2H), 3.62 (t, J=4.7 Hz, 2H), 3.36 (s, 3H);¹³C NMR (75 MHz, CDCl₃ δ 177.2, 155.5, 155.1, 153.7, 149.5, 142.1,137.1, 132.0, 129.6, 128.9, 123.8, 123.5, 122.8, 121.6, 115.8, 110.5,110.4, 109.5, 79.8, 71.0, 68.1, 59.1, 58.5, 46.1; MS (ES+) m/z 403.0(M+1).

EXAMPLE 5.35 Synthesis of5-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5 and makingnon-critical variations using5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace5-(chloromethyl)-2-methoxypyrimidine,5-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (65%): mp 140-142° C.; ¹H NMR (300 MHz, CDCl₃) δ8.57 (d,J=4.8 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.25-7.11 (m, 4H), 7.06-6.97 (m,1H), 6.89 (d, J=7.8 Hz, 1H), 6.68-6.62 (m, 1H), 6.59-6.54 (m, 1H),6.44-6.38 (m, 1H), 5.09 (ABq, 2H), 4.87 (ABq, 2H), 4.11-4.05 (m, 2H),3.77-3.68 (m, 2H), 3.43 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 162.1,160.7, 155.6, 149.5, 142.1, 137.0, 132.4, 128.8, 123.8, 123.6, 123.5,122.7, 121.6, 121.1, 109.5, 108.2, 97.3, 80.5, 70.9, 67.6, 59.2, 57.7,46.1; MS (ES+) m/z 403.0 (M+1).

EXAMPLE 5.36 Synthesis of1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 5.30 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-f][1,4]-benzodioxine-7,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)pyridine hydrobromide to replace ethyl2-(bromomethyl)nicotinate,(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-onewas obtained (57%) as a colorless solid: mp 205-206° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.52 (d, 1H, J=4.7 Hz), 7.79 (ddd, J=7.7, 7.7, 1.7 Hz,1H), 7.35-7.20 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.93 (d, J=7.7 Hz,1H), 6.29 (ABq, 2H), 5.04 (ABq, 2H), 4.84 (ABq, 2H), 4.27 (s, 4H); ¹³CNMR (75 MHz, DMSO-d₆) δ176.7, 155.2, 149.2, 148.8, 144.6, 142.5, 137.0,131.6, 129.2, 128.6, 123.6, 122.9, 122.6, 122.4, 121.4, 114.4, 109.8,109.2, 80.2, 64.1, 63.9, 57.3, 44.8; MS (ES+) m/z 387.7 (M+1).

EXAMPLE 5.37 Synthesis of1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one

A mixture of (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride(0.324 g, 1.52 mmol) and thionyl chloride (0.174 mL, 2.39 mmol) inanhydrous dichloromethane (10 mL) was stirred at ambient temperature for16 h. The reaction mixture was concentrated in vacuo and anhydrousN,N-dimethylformamide (10 mL) was added. To this mixture was added2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one(0.300 g, 1.01 mmol), cesium carbonate (0.926 g, 2.84 mmol), potassiumiodide (0.094 g, 0.57 mmol) and anhydrous N,N-dimethylformamide (15 mL)and the mixture was heated at 90° C. for 1 h. The reaction mixture wasallowed to cool to ambient temperature, concentrated in vacuo, and theresulting residue was taken up in water (50 mL), sonicated and filtered.The solid was purified by column chromatography and eluted with a 0% to40% gradient of ethyl acetate in dichloromethane followed byrecrystallization from methanol to afford1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one(0.123 g, 27%) as a colorless solid: mp 206-207° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.72 (d, J=4.4 Hz, 1H), 8.24 (d, J=7.9 Hz, 1H), 7.55 (dd,J=7.8, 5.0 Hz, 1H), 7.26-7.20 (m, 2H), 7.01 (dd, J=11.3, 3.8 Hz, 1H),6.88 (d, J=7.6 Hz, 1H), 6.36 (s, 2H), 5.22 (ABq, 2H), 4.83 (ABq, 2H),4.27 (s, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.0, 152.6, 152.4, 148.7,144.6, 142.9, 134.9, 131.7, 129.1, 128.6, 123.5, 123.0, 122.8, 122.6,122.5, 122.0, 114.8, 110.0, 108.9, 80.1, 64.1, 63.9, 57.3, 41.8; MS(ES+) m/z 455.0 (M+1).

EXAMPLE 5.38 Synthesis of6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrimidine-2,4(1H,3H)-dione

Following the procedure as described in EXAMPLE 5.25 and makingnon-critical variations using 6-(chloromethyl)uracil to replace2-(bromomethyl)pyridine hydrobromide, andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace9-fluoro-2,3-dihydro-spiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,6-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]pyrimidine-2,4(1H,3H)-dionewas obtained (5%) as an off-white solid: mp>300° C.; ¹H NMR (300 MHz,DMSO-d₆) δ11.11 (s, 1H), 11.05 (s, 1H), 7.29 (dd, J=7.7, 7.7 Hz, 1H),7.18 (d, J=6.8 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 7.03 (dd, J=7.7,7.7 Hz, 1H), 6.66 (s, 1H), 6.26 (s, 1H), 5.90 (s, 2H), 5.14 (s, 1H),4.75 (ABq, 2H), 4.60 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.4, 164.2,155.9, 151.8, 151.5, 148.8, 142.3, 142.2, 132.1, 129.4, 124.2, 123.9,120.1, 109.8, 103.6, 101.9, 96.9, 93.8, 80.4, 57.9, 40.5; MS (ES+) m/z406.3 (M+1).

EXAMPLE 6 Synthesis of1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a stirred solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.33 g, 4.73mmol) in acetone (50 mL) and 2-butanone (10 mL) were added cesiumcarbonate (3.10 g, 9.46 mmol) and5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (1.00 g, 5.92 mmol). Thereaction was stirred at ambient temperature for 16 h, then filtered andconcentrated in vacuo to dryness. The residue was purified by flashchromatography with ethyl acetate in hexanes (15% to 50% gradient) toafford1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.43 g, 22%) as a colorless solid: mp 114-116° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.29 (dd, J=7.7, 7.7 Hz, 1H), 7.21 (d, J=7.0 Hz, 1H),7.08-7.03 (m, 2H), 6.71 (s, 1H), 6.32 (s, 1H), 5.93 (d, J=3.0 Hz, 2H),5.24 (ABq, 2H), 4.78 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.2, 174.2,170.6, 155.7, 148.8, 142.4, 142.2, 132.2, 129.3, 124.1, 123.7, 120.4,109.8, 103.5, 101.9, 93.8, 79.9, 57.9, 41.6; MS (ES+) m/z 414.1 (M+1),416.1 (M+1).

EXAMPLE 6.1 Synthesis of4′-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,4′-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (17%) as a colorless solid: mp 174-176° C.; ¹H NMR (300MHz, CDCl₃) δ 7.17 (dd, J=8.0 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.67 (d,J=7.8 Hz, 1H), 6.46 (s, 1H), 6.34 (s, 1H), 5.86 (ABq, 2H), 5.16 (ABq,2H), 4.95 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 174.9, 169.4,156.8, 149.2, 143.3, 142.1, 131.7, 130.1, 128.4, 124.5, 166.5, 107.2,103.2, 101.5, 93.2, 77.2, 58.8, 41.6; MS (ES+) m/z 447.9 (M+1), 449.9(M+1).

EXAMPLE 6.2 Synthesis of5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replacespiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-tetrahydro-2H-pyran to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole,5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.28(dd, J=7.6, 7.6 Hz, 1H), 7.15-6.97 (m, 1H), 6.75 (s, 1H), 6.47 (d, J=4.9Hz, 1H), 4.89 (dd, J=8.9, 1.8 Hz, 1H), 4.65 (dd, J=8.9, 2.9 Hz, 1H),4.03-3.60 (m, 2H), 3.44-3.32 (m, 1H), 2.19 (s, 3H), 2.05 (s, 3H),1.92-1.80 (m, 1H), 1.73-1.27 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ178.0,159.1, 143.2, 138.3, 132.6, 129.3, 128.6, 126.3, 123.9, 123.6, 123.1,111.4, 109.7, 79.7, 75.6, 68.4, 58.0, 45.7, 29.6, 25.8, 23.0, 20.3,19.4; MS (ES+) m/z 364.3 (M+1).

EXAMPLE 6.3 Synthesis of1′-[(3-chlorothiophen-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using 3-chloro-2-chloromethylthiophene (Mortonet al. Tetrahedron Lett. (2000), 41:3029-3034) to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole,1′-[(3-chlorothiophen-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (38%) as an off-white solid: mp 161-163° C.; ¹H NMR (300MHz, CDCl₃) δ 7.29-7.20 (m, 2H), 7.15 (d, J=7.3 Hz, 1H), 7.08-6.93 (m,2H), 6.88 (d, J=5.2 Hz, 1H), 6.51 (s, 1H), 6.16 (s, 1H), 5.86 (d, J=2.7Hz, 2H), 5.09 (ABq, 2H), 4.80 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.3,156.0, 148.9, 142.4, 141.2, 132.1, 131.4, 129.0, 127.6, 125.1, 124.1,124.0, 123.7, 119.3, 109.2, 103.2, 101.5, 93.6, 80.5, 58.3, 37.0; MS(ES+) m/z 412.1 (M+1).

EXAMPLE 6.4 Synthesis of1′-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-methyl isoxazole to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, and acetone as the solvent,1′-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 190-192° C.; ¹H NMR (300MHz, CDCl₃) δ7.39-7.22 (m, 3H), 7.10-7.01 (m, 1H), 7.00-6.88 (m, 2H),6.46 (s, 1H), 6.20 (d, J=8.2 Hz, 1H), 6.02 (s, 1H), 5.83 (d, J=4.1 Hz,2H), 4.59 (ABq, 2H), 4.58 (ABq, 2H), 2.64 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ177.4, 169.2, 158.6, 156.0, 148.9, 142.3, 141.5, 136.0, 135.6,131.8, 131.6, 128.6, 128.3, 128.1, 127.9, 123.9, 123.2, 119.0, 110.2,107.7, 103.1, 101.5, 93.6, 80.6, 57.9, 33.3, 11.7; MS (ES+) m/z 521.3(M+1), 523.3 (M+1).

EXAMPLE 6.5 Synthesis of1′-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using4-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, and acetone as the solvent,1′-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (36%) as a colorless solid: mp 151-153° C.; ¹H NMR (300MHz, CDCl₃) δ8.02 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.30-7.21(m, 2H), 7.17 (d, J=7.2 Hz, 1H), 7.09-7.00 (m, 2H), 6.51 (s, 1H), 6.18(s, 1H), 5.85 (s, 2H), 5.13 (ABq, 2H), 4.83 (ABq, 2H); ¹³C NMR (75 MHz,CDCl₃) δ177.4, 166.8, 155.9, 152.5, 148.9, 142.3, 141.9, 136.4, 132.2,131.7 (q, J=32.6 Hz), 128.9, 126.7, 126.0 (q, J=3.7 Hz), 125.7, 123.9,123.6, 122.1, 119.5, 117.0, 109.5, 103.1, 101.5, 93.7, 80.3, 58.3, 40.4;MS (ES+) m/z 523.4 (M+1).

EXAMPLE 6.6 Synthesis of1′-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazoleto replace 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, and 2-butanoneas the solvent,1′-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (76%) as a colorless solid: mp 151-153° C.; mp 158-160° C.;¹H NMR (300 MHz, CDCl₃) δ8.02-7.94 (m, 2H), 7.56-7.41 (m, 3H), 7.27 (dd,J=7.5, 7.5 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.5, 7.5 Hz, 1H),7.04 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 5.85 (s, 2H), 5.26(ABq, 2H), 4.83 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.3, 165.8, 161.0,155.9, 149.1, 142.5, 140.8, 132.1, 131.8, 129.3, 129.2, 127.0, 124.2,124.1, 123.3, 119.1, 109.0, 103.1, 101.6, 93.7, 80.2, 58.2, 35.1; MS(ES+) m/z 440.3 (M+1).

EXAMPLE 6.7 Synthesis of1-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, and 2-butanone as thesolvent,1′-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: mp 161-162° C.; ¹H NMR (300MHz, CDCl₃) δ7.91 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.27 (dd,J=7.7, 7.7 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.07 (d, J=7.5, 7.5 Hz, 1H),7.04 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.17 (s, 1H), 5.85 (s, 2H), 5.25(ABq, 2H), 4.82 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.3, 165.0, 161.2,155.9, 149.1, 142.5, 140.7, 138.4, 131.8, 129.6, 129.3, 128.3, 124.3,124.2, 121.7, 119.1, 109.0, 103.0, 101.6, 93.7, 80.2, 58.2, 35.0; MS(ES+) m/z 474.2 (M+1), 476.2 (M+1).

EXAMPLE 6.8 Synthesis of1′-([1,3]oxazolo[4,5-b]pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 6 and makingnon-critical variations using2-(chloromethyl)[1,3]oxazolo[4,5-b]pyridine to replace5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, and 2-butanone as thesolvent,1′-([1,3]oxazolo[4,5-b]pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (11%) as a colorless solid: mp 202-204° C.; ¹H NMR (300MHz, CDCl₃) δ8.56 (d, J=4.9 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.34-7.16(m, 3H), 7.06 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.51 (s,1H), 6.28 (s, 1H), 5.86 (d, J=3.6 Hz, 2H), 5.30 (ABq, 2H), 4.85 (ABq,2H); ¹³C NMR (75 MHz, CDCl₃) δ117.4, 163.3, 155.9, 155.0, 149.1, 146.9,143.4, 142.4, 141.0, 131.9, 129.2, 127.8, 124.1, 120.7, 119.2, 118.8,109.0, 103.3, 101.6, 93.6, 80.4, 58.3, 38.0; MS (ES+) m/z 414.3 (M+1).

EXAMPLE 7 Synthesis of1′-(4-methoxybenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(1.99 g, 7.08 mmol), 4-methoxybenzyl chloride (1.30 mL, 9.6 mmol),potassium iodide (0.17 g, 0.99 mmol) and cesium carbonate (4.68 g, 14.4mmol) in 2-butanone (45 mL) was stirred at reflux under nitrogen for 16h. The reaction was cooled, diluted with ethyl acetate and filteredthrough Celite. The filtrate was concentrated under reduced pressure andthe residue was purified by flash column chromatography withhexanes/ethyl acetate (4:1) to afford1′-(4-methoxybenzyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(2.52 g, 89%) as a colorless solid: mp 147-148° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) δ7.28 (d, J=8.7 Hz, 2H), 7.21 (ddd, J=7.8, 7.5, 1.2 Hz,1H), 7.16 (dd, J=7.5, 0.6 Hz, 1H), 7.02 (ddd, J=7.7, 7.4, 1.0 Hz, 1H),6.88 (d, J=8.7 Hz, 2H), 6.83 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.13 (s,1H), 5.88 (d, J=1.2 Hz, 1H), 5.87 (d, J=1.2 Hz, 1H), 5.02 (d, J=15.3 Hz,1H), 4.97 (d, J=9.0 Hz, 1H), 4.76 (d, J=15.3 Hz, 1H), 4.69 (d, J=9.0 Hz,1H), 3.79 (s, 3H); MS (ES+) m/z 402.2 (M+1).

EXAMPLE 7.1 Synthesis of1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and3-(trifluoromethyl)benzyl chloride to replace 4-methoxybenzyl chloride,1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (92%) as a colorless solid: mp 131-134° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.62-7.43 (m, 4H), 7.25-7.18(m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.52 (s,1H), 6.23 (s, 1H), 5.14 (d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.88(d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.23-4.18 (m, 2H), 4.15-4.11(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.4, 144.8, 141.8, 138.5,137.0, 132.3, 131.4 (q, J=32.4 Hz), 130.7, 129.7, 129.0, 124.9 (q, J=3.7Hz), 124.25, 124.22 (q, J=3.7 Hz), 124.0 (q, J=272.4 Hz), 123.8, 120.9,111.6, 109.1, 99.6, 80.2, 64.7, 64.0, 58.2, 43.8; MS (ES+) m/z 453.9(M+1).

EXAMPLE 7.2 Synthesis of methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate

Following the procedure as described in EXAMPLE 7 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, andmethyl 5-(chloromethyl)-2-furoate to replace 4-methoxybenzyl chloride,methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylatewas obtained (92%) as a colorless solid: mp 88-92° C. (hexanes/diethylether); ¹H NMR (300 MHz, CDCl₃) δ7.28 (ddd, J=7.8, 7.5, 1.2 Hz, 1H),7.17 (dd, J=7.2, 0.9 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H), 7.06 (ddd, J=7.8,7.8, 0.9 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.37 (d, J=3.6Hz, 1H), 6.24 (s, 1H), 5.12 (d, J=16.5 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H),4.90 (d, J=16.5 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.18 (m, 2H),4.14-4.10 (m, 2H), 3.89 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 158.9,155.3, 153.4, 144.8, 144.4, 141.4, 138.4, 132.2, 129.1, 124.1, 123.9,120.9, 119.1, 111.7, 110.3, 109.1, 99.5, 80.1, 64.6, 64.0, 58.1, 52.1,37.4; MS (ES+) m/z 433.9 (M+1).

EXAMPLE 7.3 Synthesis of(S)-1-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A suspension of(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.0 g, 3.4 mmol), cesium carbonate (3.3 g, 10.2 mmol) and1-bromopentane (1.02 g, 6.77 mmol) in anhydrous 1,4-dioxane (25 mL) washeated at reflux under nitrogen for 2 h. The reaction mixture wasallowed to cool to ambient temperature, filtered and concentrated invacuo. Purification of the residue by column chromatography and elutedwith a 15% to 50% gradient of ethyl acetate in hexanes, followed byrecrystallization from methanol afforded(S)-1-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneas an off-white solid (0.89 g, 72%): mp 111-113° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.23-7.30 (m, 1H), 7.13 (dd,J=7.4, 0.9 Hz, 1H), 7.00-7.03 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.46 (s,1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.19-4.05 (m, 4H), 3.86-3.59 (m, 2H),1.82-1.62 (m, 2H), 1.43-1.28 (m, 4H), 0.89 (t, J=6.9 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9,123.0, 121.1, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 29.0,27.1, 22.3, 14.0; MS (ES+) m/z 366.0 (M+1).

EXAMPLE 7.4 Synthesis of(R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using(R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (74%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.25-7.30 (m, 1H), 7.16-7.11 (m, 1H), 6.99-7.04 (m, 1H), 6.89 (d, J=7.8Hz, 1H), 6.47 (s, 1H), 6.19 (s, 1H), 4.73 (ABq, 2H), 4.20-4.06 (m, 4H),3.86-3.59 (m, 2H), 1.82-1.63 (m, 2H), 1.42-1.28 (m, 4H), 0.89 (t, J=6.8Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 155.2, 144.5, 142.4, 138.2,132.5, 128.7, 123.9, 123.0, 121.2, 111.4, 108.5, 99.3, 80.1, 64.5, 63.9,58.0, 40.3, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 366.1 (M+1).

EXAMPLE 7.5 Synthesis oft-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-bromohexane to replace 1-bromopentane,1′-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.25-7.29 (dt, J=7.74, 7.71, 1.05 Hz, 1H), 7.13 (d, J=7.4 Hz, 1H),6.98-7.04 (m, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 1H),4.73 (ABq, 2H), 4.19-4.05 (m, 4H), 3.86-3.59 (m, 2H), 1.80-1.63 (m, 2H),1.44-1.22 (m, 6H), 0.87 (t, J=6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)δ177.2, 155.2, 144.5, 142.4, 138.2, 132.5, 128.7, 123.9, 123.0, 121.2,111.4, 108.5, 99.3, 80.1, 64.5, 63.9, 58.0, 40.3, 31.4, 27.4, 26.5,22.5, 14.0; MS (ES+) m/z 379.9 (M+1).

EXAMPLE 7.6 Synthesis of1′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-cyclopropylethyl 4-methylbenzenesulfonate to replace1-bromopentane,1′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (59%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.12(d, J=7.4 Hz, 2H), 6.96-7.04 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s,1H), 6.19 (s, 1H), 4.72 (ABq, 2H), 4.19-4.03 (m, 4H), 3.94-3.71 (m, 2H),0.79-0.64 (m, 1H), 0.50-0.37 (m, 2H), 0.11-0.04 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ177.2, 155.2, 144.5, 142.6, 138.2, 132.4, 128.7, 123.9,123.0, 121.1, 111.5, 108.5, 99.3, 80.1, 64.5, 63.9, 57.9, 40.4, 32.4,8.6, 4.4; MS (ES+) m/z 364.0 (M+1).

EXAMPLE 7.7 Synthesis of1-(2-ethoxyethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-bromo-2-ethoxyethane to replace 1-bromopentane,1-(2-ethoxyethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (50%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.31-7.21 (m, 1H), 7.14-7.09 (m, 1H), 7.07-6.97 (m, 2H), 6.46 (s, 1H),6.21 (s, 1H), 4.74 (ABq, 2H), 4.19-4.05 (m, 4H), 4.03-3.80 (m, 2H),3.74-3.61 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.14 (t, J=7.0 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ177.5, 155.1, 144.5, 142.6, 138.2, 132.3, 128.6,123.6, 123.1, 121.2, 111.5, 109.2, 99.2, 80.0, 67.4, 66.6, 64.5, 63.9,57.9, 40.4, 15.1; MS (ES+) m/z 368.1 (M+1).

EXAMPLE 7.8 Synthesis of1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-bromo-4-methoxybutane to replace 1-bromopentane,1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (93%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30-6.86 (m, 4H), 6.45 (s, 1H), 6.18 (s, 1H), 4.72 (ABq, 2H), 4.18-4.04(m, 4H), 3.88-3.63 (m, 2H), 3.44-3.37 (m, 2H), 3.30 (s, 3H), 1.88-1.56(m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 155.2, 144.5, 142.3, 138.2,132.5, 128.8, 123.9, 123.1, 121.1, 111.4, 108.6, 99.3, 80.1, 72.0, 64.5,63.9, 58.6, 57.9, 40.0, 26.9, 24.3; MS (ES+) m/z 381.9 (M+1).

EXAMPLE 7.9 Synthesis of1-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-bromo-3-methoxypropane to replace 1-bromopentane,1′-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30-6.93 (m, 4H), 6.46 (s, 1H), 6.18 (s, 1H), 4.72 (ABq, 2H), 4.19-4.04(m, 4H), 3.94-3.72 (m, 2H), 3.41 (t, J=5.9 Hz, 2H), 3.30 (s, 3H),2.01-1.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.3, 155.2, 144.5, 142.5,138.2, 132.4, 128.8, 123.8, 123.1, 121.1, 111.4, 108.5, 99.3, 80.0,69.7, 64.5, 63.9, 58.7, 57.9, 37.6, 27.8; MS (ES+) m/z 367.9 (M+1).

EXAMPLE 7.10 Synthesis of1′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-3-nitrobenzene to replace 1-bromopentane,1-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.19(s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.60-7.66 (m,1H), 7.28-6.97 (m, 4H), 6.49 (s, 1H), 6.13 (s, 1H), 5.07 (ABq, 2H), 4.73(ABq, 2H), 4.18-4.03 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 155.2,148.4, 144.7, 142.3, 139.1, 138.3, 134.2, 132.1, 130.8, 129.3, 124.2,123.7, 122.9, 122.3, 121.5, 111.5, 109.8, 99.3, 79.9, 64.6, 64.0, 57.7,42.8; MS (ES+) m/z 430.9 (M+1).

EXAMPLE 7.11 Synthesis of1′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 5-(chloromethyl)thiazole to replace 1-bromopentane,1′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (56%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.72(s, 1H), 7.89 (s, 1H), 7.29-6.86 (m, 4H), 6.47 (d, J=2.0 Hz, 1H), 6.16(d, J=2.0 Hz, 1H), 5.13 (ABq, 2H), 4.74 (ABq, 2H), 4.20-4.03 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ 177.0, 155.2, 153.8, 144.7, 142.6, 141.0,138.3, 133.0, 132.2, 128.9, 124.1, 123.8, 120.7, 111.5, 108.7, 99.4,79.9, 64.5, 63.9, 57.9, 36.2; MS (ES+) m/z 392.4 (M+1).

EXAMPLE 7.12 Synthesis of1′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(chloromethyl)-5-(trifluoromethyl)pyridine to replace1-bromopentane,1′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (53%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.83(s, 1H), 7.89 (dd, J=8.2, 2.0 Hz, 1H), 7.42-6.81 (m, 5H), 6.50 (s, 1H),6.28 (s, 1H), 5.13 (ABq, 2H), 4.80 (ABq, 2H), 4.22-4.07 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 177.6, 159.4, 155.2, 146.5, 146.5, 144.7, 141.7,138.3, 134.3, 134.3, 134.2, 132.1, 128.9, 126.1, 125.6, 125.1, 124.0,123.7, 121.4, 120.8, 111.6, 109.2, 99.4, 80.0, 64.5, 63.9, 58.1, 45.7;MS (ES+) m/z 454.9 (M+1).

EXAMPLE 7.13 Synthesis of1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride toreplace 1-bromopentane,1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (40%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.62(d, J=4.7 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.32-6.96 (m, 4H), 6.71-6.54(m, 2H), 6.48 (s, 1H), 5.22-5.28 (m, 2H), 4.80-4.90 (m, 2H), 4.21-4.06(m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1, 155.1, 152.3, 144.5, 142.3,138.2, 134.3, 134.2, 134.1, 134.1, 132.7, 129.2, 128.6, 125.6, 124.9,124.5, 124.1, 123.8, 123.6, 123.2, 122.1, 122.0, 121.6, 112.4, 108.5,99.1, 80.0, 64.5, 63.9, 58.2, 42.2, 42.2; MS (ES+) m/z 454.8 (M+1).

EXAMPLE 7.14 Synthesis of1′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 5-(chloromethyl)-3-(pyridin-3-yl)isoxazole to replace1-bromopentane,1′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (40%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) 8.96(s, 1H), 8.65 (d, J=4.7 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.39-6.98 (m,5H), 6.58 (s, 1H), 6.47 (s, 1H), 6.20 (s, 1H), 5.10 (ABq, 2H), 4.76(ABq, 2H), 4.20-4.03 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.2, 167.7,160.3, 155.2, 151.2, 147.9, 144.7, 141.0, 138.3, 134.0, 131.9, 129.1,124.7, 124.1, 124.1, 123.7, 120.5, 111.5, 108.8, 100.9, 99.4, 79.9,64.5, 63.8, 57.9, 35.8; MS (ES+) m/z 453.9 (M+1).

EXAMPLE 7.15 Synthesis of(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using(R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride toreplace 1-bromopentane,(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.63(d, J=4.5 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.34-6.96 (m, 4H), 6.62 (s,1H), 6.59 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 5.26 (ABq, 2H), 4.85 (, 2H),4.21-4.08 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1, 155.1, 152.3, 144.5,142.3, 138.2, 134.3, 134.2, 134.1, 134.0, 132.7, 128.5, 125.6, 124.9,124.5, 124.1, 123.8, 123.2, 122.1, 122.0, 121.6, 112.4, 108.5, 99.1,80.0, 64.5, 63.9, 58.2, 42.2, 42.2; MS (ES+) m/z 454.8 (M+1).

EXAMPLE 7.16 Synthesis ofN,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′-(2′H)-yl)methyl]benzenesulfonamide

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one,and 3-(chloromethyl)-N,N-dimethylbenzenesulfonamide to replace1-bromopentane,N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1-(2′H)-yl)methyl]benzenesulfonamidewas obtained (40%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.72-7.62 (m, 4H), 7.29-6.99 (m, 4H), 6.50 (s, 1H), 6.07 (s, 1H), 5.06(ABq, 2H), 4.71 (ABq, 2H), 4.19-4.05 (m, 4H), 2.50 (s, 6H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.9, 154.7, 144.2, 141.9, 137.8, 134.9, 131.8, 131.5,129.9, 128.8, 126.6, 125.9, 123.8, 123.2, 120.9, 110.9, 109.3, 98.8,79.4, 64.2, 63.5, 57.2, 42.5, 37.4; MS (ES+) m/z 492.7 (M+1).

EXAMPLE 7.17 Synthesis of1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 4-(3-(chloromethyl)phenylsulfonyl)morpholine to replace1-bromopentane,1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-onewas obtained (40%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.73-7.64 (m, 4H), 7.29-7.18 (m, 2H), 7.05 (dd, J=7.3, 5.6 Hz, 2H), 6.52(s, 1H), 6.11 (s, 1H), 5.09 (ABq, 2H), 4.74 (dd, J=9.3 Hz, 2H),4.04-4.21 (m, 4H), 3.56 (t, J=4.5 Hz, 4H), 2.84-2.65 (m, 4H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.9, 154.8, 144.2, 141.9, 138.0, 137.9, 134.7,132.2, 131.6, 130.1, 128.8, 126.7, 125.9, 123.9, 123.3, 121.0, 110.9,109.5, 98.9, 79.5, 65.2, 64.2, 63.6, 57.3, 45.8, 42.5; MS (ES+) m/z534.9 (M+1).

EXAMPLE 7.18 Synthesis of1′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 3-(chloromethyl)-4-methyl-1,2,5-oxadiazole to replace1-bromopentane,1′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (69%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.36-7.28 (m, 1H), 7.22-7.03 (m, 3H), 6.52 (s, 1H), 6.23 (s, 1H), 5.19(ABq, 2H), 4.73 (ABq, 2H), 4.22-4.07 (m, 4H), 2.41 (s, 3H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.6, 154.6, 151.4, 151.3, 144.2, 141.6, 137.8, 131.8,128.7, 123.6, 123.4, 121.1, 111.2, 109.3, 98.7, 79.3, 64.2, 63.6, 57.2;MS (ES+) m/z 414.0 (M+23).

EXAMPLE 7.19 Synthesis of1-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2,3-difluorobenzene to replace 1-bromopentane,1-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.45-7.10 (m, 5H), 7.01-7.08 (m, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.52 (s,1H), 6.14 (s, 1H), 5.04 (ABq, 2H), 4.74 (ABq, 2H), 4.22-4.06 (m, 4H);¹³C NMR (75 MHz, DMSO-d₆) δ 176.6, 154.7, 144.2, 141.9, 137.8, 131.6,128.9, 125.7, 125.6, 125.2, 124.4, 123.7, 123.2, 121.0, 116.9, 116.7,111.1, 109.1, 98.8, 79.5, 64.2, 63.6, 57.2; MS (ES+) m/z 421.8 (M+1).

EXAMPLE 7.20 Synthesis of1′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-3,5-difluorobenzene to replace 1-bromopentane,1′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (72%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.22-7.32 (m, 1H), 7.24-7.14 (m, 2H), 7.13-7.00 (m, 4H), 6.53 (s, 1H),6.11 (s, 1H), 4.96 (s, 2H), 4.77 (ABq, 2H), 4.23-4.07 (m, 4H); ¹³C NMR(75 MHz, DMSO-d₆) δ 176.6, 154.7, 144.2, 141.9, 137.8, 131.6, 128.9,125.7, 125.6, 125.2, 124.4, 123.7, 123.2, 121.0, 116.9, 116.7, 111.1,109.1, 98.8, 79.5, 64.2, 63.6, 57.2; MS (ES+) m/z 421.8 (M+1).

EXAMPLE 7.21 Synthesis of1′-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-4-fluorobenzene to replace 1-bromopentane,1-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.45-7.37 (m, 2H), 7.31-7.23 (m, 1H), 7.23-7.14 (m, 3H), 7.07-6.99 (m,2H), 6.53 (s, 1H), 6.09 (s, 1H), 4.92 (ABq, 2H), 4.74 (ABq, 2H),4.22-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.7, 154.7, 144.2,142.1, 137.8, 132.6, 132.5, 132.0, 129.4, 129.3, 128.8, 123.7, 123.1,121.2, 115.7, 115.4, 111.0, 109.4, 98.8, 79.4, 64.2, 63.6, 57.2, 42.4;MS (ES+) m/z 403.8 (M+1).

EXAMPLE 7.22 Synthesis of1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2-chloro-4-fluorobenzene to replace 1-bromopentane,1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (81%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.52-7.60 (m, 1H), 7.35-7.17 (m, 4H), 7.10-7.02 (m, 1H), 6.89 (d, J=7.8Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 4.97 (ABq 2H), 4.75 (ABq, 2H),4.22-4.08 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.7, 154.8, 144.2,142.1, 137.8, 132.9, 131.7, 130.1, 129.5, 129.4, 128.9, 123.8, 123.2,121.0, 117.2, 116.9, 114.9, 111.3, 109.3, 98.8, 79.6, 64.2, 63.6, 57.2,41.1; MS (ES+) m/z 437.6 (M+1).

EXAMPLE 7.23 Synthesis of1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 5-(chloromethyl)-1-methyl-1H-benzo[d][1,2,3]triazole to replace1-bromopentane,1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (15%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.08 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.6, 1.2 Hz, 1H),7.20-7.28 (m, 1H), 7.18 (d, J=6.9 Hz, 1H), 7.08 (d, J=7.7 Hz, 1H), 7.02(t, J=7.4 Hz, 1H), 6.54 (s, 1H), 6.08 (s, 1H), 5.10 (ABq, 2H), 4.77(ABq, 2H), 4.28 (s, 3H), 4.22-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 154.7, 145.2, 144.2, 142.0, 137.8, 132.9, 132.4, 131.7, 128.8,126.7, 123.7, 123.1, 121.2, 117.6, 111.3, 110.9, 109.5, 98.9, 79.4,64.2, 63.6, 57.3, 43.1, 34.2; MS (ES+) m/z 440.9 (M+1).

EXAMPLE 7.24 Synthesis of1′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-3-(trifluoromethoxy)benzene to replace1-bromopentane,1′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (62%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.47-7.55 (m, 1H), 7.41-7.34 (m, 2H), 7.33-7.24 (m, 2H), 7.22-7.17 (m,1H), 7.09-7.00 (m, 2H), 6.53 (s, 1H), 6.08 (s, 1H), 5.00 (ABq, 2H), 4.75(ABq, 2H), 4.22-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.9, 154.7,148.6, 148.5, 144.2, 142.0, 139.3, 137.9, 131.6, 130.8, 128.8, 126.2,123.7, 123.2, 121.1, 120.1, 120.0 (q, J_(C-F)=256.4 Hz), 119.7, 110.9,109.3, 98.8, 79.4, 64.2, 63.6, 57.2, 42.5; MS (ES+) m/z 469.9 (M+1).

EXAMPLE 7.25 Synthesis oft-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1W)-one,and 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene to replace1-bromopentane,1′-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.73-7.53 (m, 3H), 7.24 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.16 (dd, J=7.3,0.9 Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.51 (s,1H), 6.14 (s, 1H), 5.14 (ABq, 2H), 4.67 (ABq, 2H), 4.22-4.07 (m, 4H);¹³C NMR (75 MHz, DMSO-d₆) δ 176.4, 163.0, 159.7, 154.7, 144.2, 142.2,137.8, 131.7, 130.7, 130.6, 129.4, 129.3, 129.0, 128.7, 125.4, 125.3,123.7, 123.0, 122.7, 121.7, 121.5, 121.0, 120.8, 120.5, 111.2, 108.6,98.7, 79.6, 64.2, 63.6, 56.9, 36.3; MS (ES+) m/z 471.8 (M+1).

EXAMPLE 7.26 Synthesis of1′-[(2-fluoro-5-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene to replace1-bromopentane,1′-[(2-fluoro-5-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (75%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.84-7.76 (m, 1H), 7.75-7.69 (m, 1H), 7.50-7.55 (m, 1H), 7.26-7.33 (m,1H), 7.20 (d, J=6.8 Hz, 1H), 7.10-7.00 (m, 2H), 6.53 (s, 1H), 6.05 (s,1H), 5.08 (ABq, 2H), 4.74 (ABq, 2H), 4.22-4.06 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.7, 164.0, 160.7, 154.7, 144.2, 141.8, 137.9, 131.6,128.9, 127.5, 127.47, 127.39, 127.3, 126.9, 126.8, 126.7, 126.2, 126.1,125.7, 125.6, 125.3, 125.2, 124.8, 124.6, 123.8, 123.7 (q, J_(C-F)=271.8Hz), 123.3, 121.1, 117.3, 116.9, 110.8, 109.1, 98.9, 79.4, 64.2, 63.6,57.2, 37.7; MS (ES+) m/z 471.8 (M+1).

EXAMPLE 7.27 Synthesis of1′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 1-(bromomethyl)-2-(trifluoromethoxy)benzene to replace1-bromopentane,1′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (42%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.51-7.33 (m, 4H), 7.21-7.29 (m, 1H), 7.19 (d, J=7.1 Hz, 1H), 7.02-7.06(m, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.21 (s, 1H), 5.00 (ABq,2H), 4.75 (ABq, 2H), 4.22-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.7, 154.7, 146.4, 144.2, 142.1, 137.8, 131.7, 129.6, 129.1, 128.8,128.3, 127.8, 123.7, 123.2, 121.1, 120.9, 120.2, (q, J_(C-F) 253.9 Hz),111.3, 109.0, 98.8, 79.5, 64.2, 63.6, 57.2; MS (ES+) m/z 469.8 (M+1).

EXAMPLE 7.28 Synthesis of1′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 7.3 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(2-bromoethyl)-2,5,5-trimethyl-1,3-dioxane to replace1-bromopentane,1′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (23%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.33-7.38 (m, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.04 (t, J=6.9 Hz, 2H), 6.50(s, 1H), 6.14 (s, 1H), 4.67 (ABq, 2H), 4.22-4.05 (m, 4H), 3.96-3.71 (m,2H), 3.49 (ABq, 4H), 2.09-1.84 (m, 2H), 1.41 (s, 3H), 1.00 (s, 3H), 0.82(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.2, 154.6, 144.1, 142.3, 137.8,132.0, 128.9, 123.6, 122.7, 121.3, 111.2, 108.7, 98.7, 97.5, 79.3, 69.4,64.2, 63.6, 57.1, 35.6, 34.9, 29.5, 22.6, 21.9, 19.7; MS (ES+) m/z 451.7(M+1).

EXAMPLE 8 Synthesis of1′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.30 g, 1.07 mmol) and cesium carbonate (0.56 g, 1.71 mmol) inN,N-dimethylformamide (7 mL) was stirred at ambient temperature undernitrogen for 40 min. To this mixture was added potassium iodide (0.05 g,0.28 mmol) and (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate(0.38 g, 1.40 mmol). The reaction was warmed to 60° C. and stirred for 2h. The solvent was removed under reduced pressure, and the residue wassuspended in ethyl acetate and filtered through Celite. The filtrate wasconcentrated under reduced pressure and the product was purified byflash column chromatography with dichloromethane/t-butyl methyl ether(19:1) to afford1′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.38 g, 93%) as a colorless solid: mp 147-149° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ7.34-7.28 (m,1H), 7.17 (d, J=7.2 Hz, 1H), 7.09-7.02 (m, 2H), 6.51 (s, 1H), 6.16, 6.12(s, 1H), 5.89-5.86 (m, 2H), 4.81, 4.80 (2ABq, 2H), 3.99-3.55 (m, 8H),3.46-3.38 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ178.0,177.9, 156.0, 155.9, 149.01, 148.98, 142.7, 142.6, 142.5, 142.4, 132.3,132.2, 129.02, 128.97, 123.94, 123.87, 123.6, 119.7, 119.5, 109.6,109.4, 103.14, 103.07, 101.64, 101.62, 93.74, 93.72, 80.5, 80.4, 73.3,73.2, 69.4, 69.2, 66.8, 66.7, 66.53, 66.49, 58.3, 58.2, 41.9, 41.7; MS(ES+) m/z 381.9 (M+1).

EXAMPLE 8.1 Synthesis of7′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,7′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (98%) as a colorless solid: mp 192-193° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, DMSO-d₆) δ7.23-7.18 (m, 1H), 7.08-6.98 (m,2H), 6.53 (d, J=17.6 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 4.80-4.69 (m, 2H),4.53-4.47 (m, 2H), 4.20-4.11 (m, 1H), 3.95-3.60 (m, 4H), 2.99-2.93 (m,2H), 2.04-1.59 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.7, 177.6, 161.1(2C), 160.5, 160.3, 138.3, 138.0, 135.8, 135.4, 130.7, 130.6, 124.1,122.7, 122.6, 120.5, 120.2, 119.9, 119.8, 119.2, 118.8, 114.3, 114.2,92.4, 92.2, 80.0, 76.3, 76.1, 72.0, 72.0, 67.2, 66.9, 56.7, 56.5, 45.0,44.9, 28.3, 28.2, 24.9, 24.9; MS (ES+) m/z 397.7 (M+1), 399.7 (M+1).

EXAMPLE 8.2 Synthesis of7′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using7′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,7′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (28%) as a colorless solid: mp 169-170° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ7.35-7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.56(d, J=28.1 Hz, 1H), 6.41 (d, J=2.9 Hz, 1H), 4.78-4.67 (m, 2H), 4.52-4.46(m, 2H), 4.30-3.93 (m, 3H), 3.82-3.93 (m, 2H), 2.99-2.91 (m, 2H),2.06-1.58 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.7, 156.8, 156.7,154.3, 142.9, 142.7, 136.1, 136.0, 132.8, 131.5, 131.3, 128.7 (2C),123.3 (2C), 122.7, 121.9, 121.8, 109.7, 109.6, 109.5, 104.5, 104.4,92.4, 79.5, 75.6, 75.4, 67.1, 67.0, 57.2, 43.8, 43.7, 28.5, 28.4, 28.1,25.0, 24.9.

EXAMPLE 8.3 Synthesis of4′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using4′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,4′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (76%) as a colorless solid: mp 175-176° C. (diethyl ether);¹H NMR (300 MHz, CD₃OD) δ7.14-7.06 (m, 1H), 6.71-6.52 (m, 2H), 6.25 (d,J=2.3 Hz, 1H), 4.80-4.78 (m, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.26-3.69 (m,5H), 3.00 (t, J=8.6 Hz, 2H), 2.56 (s, 3H), 2.16-1.87 (m, 3H), 1.78-1.69(m, 1H); MS (ES+) m/z 396.0 (M+1).

EXAMPLE 8.4 Synthesis of1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and1-bromopentane to replace (R)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate,1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (91%) as a colorless solid: mp 129-130° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.29 (ddd, J=8.0, 7.7, 1.5 Hz,1H), 7.16 (d, J=7.5 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d,J=7.8 Hz, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.63(d, J=9.0 Hz, 1H), 4.23-4.17 (m, 2H), 4.14-4.09 (m, 2H), 3.87-3.77 (m,1H), 3.72-3.62 (m, 1H), 1.77-1.68 (m, 2H), 1.45-1.30 (m, 4H), 0.91 (t,J=6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.3, 155.3, 144.6, 142.5,138.3, 132.7, 128.9, 124.0, 123.2, 121.3, 111.6, 108.7, 99.4, 80.2,64.6, 64.0, 58.1, 40.4, 29.1, 27.2, 22.4, 14.1; MS (ES+) m/z 366.0(M+1).

EXAMPLE 8.5 Synthesis of(8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using(R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (S)-2-(iodomethyl)-1,4-dioxane (Kim, H. Y. et al., Bioorg. Med.Chem. Lett. (2005), 15:3207-11) to replace (R)-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate,(8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (51%) as a colorless solid: mp 198-199° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.8, 7.8, 1.1 Hz,1H), 7.16 (d, J=7.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H), 6.24 (s,1H), 4.88 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H),4.13-4.08 (m, 2H), 3.98-3.78 (m, 4H), 3.75-3.56 (m, 4H), 3.47-3.38 (m,1H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 155.3, 144.7, 142.7, 138.4, 132.4,128.9, 123.8, 123.5, 121.3, 111.7, 109.6, 99.5, 80.1, 73.3, 69.2, 66.7,66.5, 64.6, 64.0, 58.1, 41.8; MS (ES+) m/z 396.0 (M+1).

EXAMPLE 8.6 Synthesis of(8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using(R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,(8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (88%) as a colorless solid: mp 207-209° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz,1H), 7.15 (dd, J=7.5, 0.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H), 6.21(s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.21-4.16 (m,2H), 4.13-4.08 (m, 2H), 3.98-3.79 (m, 4H), 3.75-3.56 (m, 4H), 3.41 (dd,J=11.6, 9.8 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.3, 144.7,142.7, 138.4, 132.3, 128.9, 123.9, 123.5, 121.1, 111.6, 109.4, 99.5,80.2, 73.3, 69.4, 66.8, 66.5, 64.6, 64.0, 58.0, 41.9; MS (ES+) m/z 396.0(M+1).

EXAMPLE 8.7 Synthesis of(8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,(8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (92%) as a colorless solid: mp 198-200° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.30 (ddd, J=7.8, 7.5, 1.2 Hz,1H), 7.15 (dd, J=7.5, 1.2 Hz, 1H), 7.08-7.01 (m, 2H), 6.49 (s, 1H), 6.24(s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.21-4.16 (m,2H), 4.14-4.09 (m, 2H), 3.98-3.79 (m, 4H), 3.74-3.55 (m, 4H), 3.42 (dd,J=11.6, 9.5 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 155.2, 144.7,142.7, 138.4, 132.4, 128.9, 123.8, 123.5, 121.3, 111.7, 109.6, 99.5,80.0, 73.3, 69.2, 66.7, 66.5, 64.6, 64.0, 58.1, 41.8; MS (ES+) m/z 396.0(M+1).

EXAMPLE 8.8 Synthesis of(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (84%) as a colorless solid: mp 207-210° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.30 (ddd, J=7.7, 7.7, 1.2 Hz,1H), 7.15 (dd, J=7.5 Hz, 0.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H),6.21 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.21-4.16(m, 2H), 4.13-4.09 (m, 2H), 3.98-3.77 (m, 4H), 3.75-3.56 (m, 4H), 3.41(dd, J=11.7, 9.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ177.8, 155.3, 144.7,142.7, 138.4, 132.3, 128.9, 123.9, 123.5, 121.1, 111.6, 109.4, 99.5,80.2, 73.3, 69.4, 66.8, 66.5, 64.6, 64.0, 58.0, 41.9; MS (ES+) m/z 396.0(M+1).

EXAMPLE 8.9 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (57%) as a colorless solid: mp 162-164° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ7.29 (dd,J=7.8, 7.8 Hz, 1H), 7.16-7.00 (m, 3H), 6.79 (s, 1H), 6.12 (s, 1H), 4.91(d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.48 (t, J=8.7 Hz, 2H),4.31-4.22 (m, 1H), 4.00-3.67 (m, 4H), 3.14 (t, J=8.7 Hz, 2H), 2.09-1.82(m, 3H), 1.78-1.67 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers)δ178.0, 177.8, 155.1, 154.9, 143.1, 142.9, 132.3, 132.2, 128.94, 128.88,128.7, 127.91, 127.86, 123.8, 123.7, 123.4, 109.9, 109.5, 107.1, 104.01,103.96, 80.2, 80.1, 77.1, 76.8, 71.7, 68.4, 68.3, 58.52, 58.49, 44.7,30.4, 29.4, 29.0, 25.9, 25.7; MS (ES+) m/z 364.0 (M+1).

EXAMPLE 8.10 Synthesis of1′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and(S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (97%) as a colorless solid: mp 162-164° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ 7.302, 7.298(ddd, J=7.8, 7.7, 1.3 Hz, 1H), 7.17-7.14 (m, 1H), 7.07-7.02 (m, 2H),6.79 (s, 1H), 6.12, 6.09 (s, 1H), 4.91, 4.90 (d, J=8.9 Hz, 1H), 4.66,4.65 (d, J=8.9 Hz, 1H), 4.48 (t, J=8.7 Hz, 2H), 3.98-3.78 (m, 4H),3.75-3.55 (m, 4H), 3.45-3.37 (m, 1H), 3.14 (t, J=8.7 Hz, 2H); ¹³C NMR(75 MHz, CDCl₃) (diastereomers) δ177.9, 177.7, 155.1, 155.0, 154.92,154.88, 142.8, 142.7, 132.3, 132.2, 128.94, 128.89, 128.84, 128.80,127.8, 127.7, 123.9, 123.8, 123.5, 109.6, 109.4, 107.19, 107.16, 104.0,103.9, 80.0, 79.9, 73.3, 71.7, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48,58.46, 58.43, 41.9, 41.8, 30.4; MS (ES+) m/z 380.0 (M+1).

EXAMPLE 8.11 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: mp 134-138° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ7.29 (dd,J=7.8, 7.8 Hz, 1H), 7.14-7.01 (m, 3H), 6.58 (s, 1H), 6.36 (s, 1H), 4.91(d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.31-4.18 (m, 2H), 4.12-4.04(m, 2H), 4.01-3.68 (m, 5H), 2.21-1.85 (m, 5H), 1.77-1.66 (m, 1H); ¹³CNMR (75 MHz, CDCl₃) (diastereomers) δ178.0, 177.8, 156.8, 153.0, 146.3,143.0, 142.9, 132.3, 132.2, 128.94, 128.90, 123.9, 123.8, 123.4, 123.34,123.28, 116.14, 116.10, 109.8, 109.6, 103.5, 80.58, 77.1, 76.9, 70.9,68.4, 68.3, 58.04, 58.02, 44.7, 32.3, 29.4, 29.1, 25.9, 25.7; MS (ES+)m/z 394.1 (M+1).

EXAMPLE 8.12 Synthesis of1′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (S)-2-(iodomethyl)-1,4-dioxane to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (61%) as a colorless solid: mp 144-147° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ 7.30 (ddd,J=7.7, 7.7, 1.0 Hz, 1H), 7.14 (d, J=6.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.59(s, 1H), 6.36, 6.33 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66(d, J=9.0 Hz, 1H), 4.28-4.19 (m, 1H), 4.15-4.02 (m, 2H), 3.99-3.78 (m,5H), 3.75-3.57 (m, 4H), 3.46-3.39 (m, 1H), 2.22-2.00 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) (diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.1,153.0, 146.4, 146.3, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0,123.9, 123.6, 123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.58, 103.56,80.5, 80.4, 73.34, 73.30, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49,57.98, 57.96, 41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).

EXAMPLE 8.13 Synthesis of1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one,and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-onewas obtained (91%) as a colorless solid: mp 137-139° C. (hexanes/diethylether); ¹H NMR (300 MHz, CDCl₃) (diastereomers) δ 7.33-7.27 (m, 1H),7.14 (d, J=7.2 Hz, 1H), 7.08-7.01 (m, 2H), 6.58 (s, 1H), 6.36, 6.33 (s,1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66 (d, J=9.0 Hz, 1H),4.28-4.20 (m, 1H), 4.14-4.02 (m, 2H), 3.99-3.78 (m, 5H), 3.76-3.57 (m,4H), 3.46-3.38 (m, 1H), 2.22-2.00 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)(diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.08, 153.05, 146.38,146.35, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0, 123.9, 123.6,123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.59, 103.56, 80.5, 80.4,73.34, 73.31, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49, 57.98, 57.96,41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).

EXAMPLE 8.14 Synthesis of3-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H-spiro[benzofuro[6,5-d]oxazole-7,3′-indoline]-2,2′(3H,6H)-dione

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dioneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace(R)-(1,4-dioxan-2-yl)methyl 4-methyl benzenesulfonate,3-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H-spiro[benzofuro[6,5-d]oxazole-7,3′-indoline]-2,2′(3H,6H)-dionewas obtained (69%) as a colorless solid: mp 186-187° C. (diethyl ether);¹H NMR (300 MHz, DMSO-d₆) δ7.36-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 1H),7.14 (d, J=8.2 Hz, 1H), 7.06-7.02 (m, 2H), 6.63 (d, J=6.9 Hz, 1H),4.85-4.73 (m, 2H), 4.24-4.16 (m, 1H), 3.81-3.59 (m, 4H), 3.31 (s, 3H),2.00-1.75 (m, 3H), 1.69-1.55 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.2,157.3, 154.9, 143.4, 136.6, 133.3, 131.9, 129.3, 123.9, 123.3, 122.3,110.2, 105.0, 92.9, 80.0, 76.1, 67.7, 57.7, 44.3, 29.1, 28.6, 25.5; MS(ES+) m/z 392.7 (M+1).

EXAMPLE 8.15 Synthesis of7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)pyridine hydrobromide to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-onewas obtained (38%) as a colorless solid: mp 205-207° C.(dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ8.55 (d, J=4.8 Hz, 1H),7.69-7.63 (m, 1H), 7.23-7.16 (m, 2H), 6.99-6.89 (m, 3H), 6.50 (s, 2H),5.35 (d, J=16.4 Hz, 1H), 5.17 (d, J=16.4 Hz, 1H), 4.97 (d, J=8.9 Hz,1H), 4.70 (d, J=8.9 Hz, 1H), 4.22-4.19 (m, 2H), 4.15-4.13 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 177.5, 155.7, 155.1, 149.6, 144.7, 138.4, 136.7,124.0, 124.0, 122.4, 121.0, 120.7, 119.7, 119.6, 116.7, 116.5, 112.1,99.3, 80.3, 64.5, 63.9, 58.4, 47.0; MS (ES+) m/z 405.0 (M+1).

EXAMPLE 8.16 Synthesis of7′-fluoro-1-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride toreplace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,7′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-onewas obtained (40%) as a colorless solid: mp 241-243° C.(dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ8.62 (d, J=4.7 Hz, 1H), 7.97(d, J=7.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.00-6.86 (m, 3H), 6.68 (s, 1H),6.50 (s, 1H), 5.54 (d, J=17.1 Hz, 1H), 5.37 (d, J=17.1 Hz, 1H), 4.99 (d,J=9.0 Hz, 1H), 4.73 (d, J=9.0 Hz, 1H), 4.21-4.19 (m, 2H), 4.15-4.14 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 155.1, 153.0, 151.9, 149.2, 145.9,144.7, 138.3, 135.5, 134.3, 129.2, 123.9, 121.9, 121.3, 119.6, 116.4,116.2, 112.5, 99.2, 80.2, 64.6, 63.9, 58.5, 44.2; MS (ES+) m/z 473.0(M+1).

EXAMPLE 8.17 Synthesis of3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and1-(bromomethyl)-2-(difluoromethyl)benzene to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-onewas obtained (52%) as a colorless solid: mp 191-193° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.67 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.37 (s, 1H),7.26-7.20 (m, 3H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H),6.53 (s, 1H), 6.24 (s, 1H), 5.17-5.04 (m, 2H), 4.77 (ABq, 2H), 4.20-4.11(m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.4, 155.3, 144.7, 142.6, 138.3,134.5 (t, J_(C-F)=3.8 Hz), 132.1, 131.9, 131.8 (t, J_(C-F)=21.3 Hz),129.3, 128.3, 127.4, 127.0 (t, J_(C-F)=7.7 Hz), 124.3, 123.7, 121.5,114.9 (t, J_(C-F)=236.0 Hz), 111.8, 109.8, 99.3, 80.1, 64.7, 64.1, 57.8;MS (ES+) m/z 435.7 (M+1).

EXAMPLE 8.18 Synthesis of1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 8 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and3-(chloromethyl)-5-fluoropyridine hydrochloride (Carlson et al., ActaPharmaceutica Suecica, 1972, 9, 411-414) to replace(R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate,1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.45-8.38 (m, 2H), 7.37-7.34 (m, 1H), 7.24-7.14 (m, 2H), 7.04-7.00 (m,1H), 6.78-6.75 (m, 1H), 6.46 (s, 1H), 6.17 (s, 1H), 5.03-4.85 (m, 3H),4.64-4.61 (m, 1H), 4.16-4.04 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6,155.3, 144.7, 144.6, 141.4, 138.4, 138.1, 137.8, 132.1, 129.0, 124.3,123.9, 122.1, 121.9, 120.6, 111.4, 108.8, 99.5, 80.1, 64.5, 63.9, 58.0,41.1; MS (ES+) m/z 405.0 (M+1).

EXAMPLE 8.19 Synthesis of(8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.40 g, 1.35 mmol) in 2-butanone (15 mL) was added cesium carbonate(1.76 g, 5.40 mmol), 3-(chloromethyl)-5-fluoropyridine hydrochloride(0.49 g, 2.69 mmol) and potassium iodide (0.085 g, 38 mol %). Thismixture was stirred under nitrogen at ambient temperature for 72 h.Further, cesium carbonate (1.76 g, 5.40 mmol),3-(chloromethyl)-5-fluoropyridine hydrochloride (0.49 g, 2.69 mmol) andtetra-n-butylammonium iodide (0.08 g, 0.22 mmol) were added and thereaction mixture was heated at reflux for 48 h, allowed to cool toambient temperature, filtered and concentrated in vacuo. The residue waspurified by column chromatography and eluted with a 10% to 40% gradientof ethyl acetate in hexanes and recrystallized from diethyl ether toafford(8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(102.1 mg, 19%) as a yellow solid: mp 197-200° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃) δ 8.48-8.42 (m, 2H), 7.40-7.37 (m, 1H), 7.26-7.17(m, 2H), 7.08-7.03 (m, 1H), 6.78-6.76 (m, 1H), 6.50 (s, 1H), 6.18 (s,1H), 5.06-4.88 (m, 3H), 4.66-4.63 (m, 1H), 4.20-4.09 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 177.7, 155.3, 144.8, 144.4, 141.3, 138.4, 138.0,137.7, 132.1, 129.0, 124.3, 124.0, 122.4, 122.2, 120.5, 111.4, 108.7,99.5, 80.1, 64.5, 63.9, 58.0, 41.1; MS (ES+) m/z 404.9 (M+1).

EXAMPLE 9 Synthesis of3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

To a stirred solution of3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.29 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added sodiumhydride (0.05 g, 1.25 mmol) at 0° C. The reaction mixture was stirred at0° C. for 30 min, then 2-(bromomethyl)-5-(trifluoromethyl)furan (0.25mL, 1.80 mmol) was added. The mixture was stirred at ambient temperaturefor 20 h, diluted with ethyl acetate, washed with water and brine, anddried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuum. The residue was purified by columnchromatography with ethyl acetate in hexanes (10% to 40% gradient) toafford3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.35 g, 80%): mp 111-112° C. (diethyl ether/hexanes); ¹H NMR (300 MHz,CDCl₃) δ7.46 (d, J=9.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.15-7.12 (m, 1H),7.06-7.01 (m, 3H), 6.77-6.76 (m, 1H), 6.55-6.52 (m, 1H), 5.20-4.85 (m,4H), 2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ175.7, 163.9, 158.1, 154.9,151.6, 141.4, 130.2, 129.5, 123.9, 123.1, 120.7, 117.9, 117.1, 112.9,109.3, 108.9, 108.8, 107.9, 81.2, 56.2, 37.5, 9.8; MS (ES+) m/z 462.9(M+23).

EXAMPLE 9.1 Synthesis of1′-[2-(2-methoxyethoxy)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and1-bromo-2-(2-methoxyethoxy)ethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one wasobtained (68%) as a colorless solid: mp 105-107° C.; 1H NMR (300 MHz,CDCl₃) δ7.32-7.24 (m, 1H), 7.18-7.12 (m, 1H), 7.07-7.00 (m, 2H), 6.49(s, 1H), 6.40 (s, 1H), 4.80 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.09-3.88(m, 2H), 3.83-3.73 (m, 2H), 3.68-3.60 (m, 2H), 3.53-3.46 (m, 2H), 3.34(s, 3H), 3.04-2.94 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 161.7,161.2, 142.5, 132.8, 128.6, 123.7, 123.2, 120.3, 119.8, 118.9, 109.1,93.1, 80.5, 72.3, 71.9, 70.3, 68.1, 59.0, 57.6, 40.1, 29.0; MS (ES+) m/z382.1 (M+1).

EXAMPLE 9.2 Synthesis of1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and(S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: mp 133-136° C.; ¹H NMR (300MHz, CDCl₃) δ7.35-7.27 (m, 1H), 7.24-7.14 (m, 1H), 7.14-7.03 (m, 1H),7.00-6.85 (m, 1H), 6.54-6.42 (m, 1H), 6.42-6.37 (m, 1H), 4.93 (t, J=9.3Hz, 1H), 4.67 (dd, J=9.3, 3.0 Hz, 1H), 4.53 (t, J=8.5 Hz, 2H), 4.18-4.04(m, 1H), 3.93 (dt, J=13.9, 4.6 Hz, 1H), 3.72 (dt, J=13.9, 4.6 Hz, 1H),3.07-2.80 (m, 3H), 2.42-2.15 (m, 3H), 2.06-1.81 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ178.6, 178.5, 161.8 (2C), 161.3, 161.2, 142.2, 142.1,132.6, 132.5, 129.0 (2C), 128.9, 128.8, 124.1, 123.6, 119.9 (3C), 119.7,118.8, 108.3, 93.2, 93.1, 80.6, 80.5, 72.3, 57.5, 53.2, 53.1, 45.2 (2C),29.6, 29.6, 28.9, 24.7 (2C); MS (ES+) m/z 377.1 (M+1).

EXAMPLE 9.3 Synthesis of1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 9 and making non-criticalvariations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(2-oxooxazolidin-3-yl)ethyl 4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (46%) as a colorless solid: mp 185-186° C.; ¹H NMR (300MHz, CDCl₃) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08(dd, J=7.3, 7.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.40 (s,1H), 4.78 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.33-4.22 (m, 1H),4.21-4.00 (m, 2H), 3.93-3.58 (m, 4H), 3.57-3.43 (m, 1H), 3.05-2.91 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.8, 161.8, 161.3, 158.7, 141.7, 132.4,129.0, 124.1, 123.7, 120.0, 119.0, 108.3, 93.2, 80.5, 72.5, 62.1, 57.7,44.3, 41.7, 37.3, 29.0; MS (ES+) m/z 393.3 (M+1).

EXAMPLE 9.4 Synthesis of1-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(4-(chloromethyl)phenyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 217-219° C.; ¹H NMR (300MHz, CDCl₃) δ 8.66 (d, J=4.3 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.78-7.64(m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.25-7.11 (m, 3H), 7.00 (dd, J=7.6, 7.6Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 6.42 (s, 1H), 5.00 (ABq,2H), 4.85 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.09-2.87 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.9, 161.7, 161.2, 156.7, 149.6, 141.9, 138.9, 136.7,136.4, 132.6, 128.6, 127.8, 127.3, 123.8, 123.4, 122.2, 120.4, 120.1,119.9, 118.8, 109.3, 93.2, 80.6, 72.3, 57.7, 43.8, 29.0; MS (ES+) m/z447.1 (M+1).

EXAMPLE 9.5 Synthesis of1′-(pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(chloromethyl)pyrimidine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,(pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (84%) as a colorless solid: mp 203-205° C.; ¹H NMR (300MHz, CDCl₃) δ8.68 (d, J=4.9 Hz, 2H), 7.24-7.15 (m, 3H), 7.03 (dd, J=7.5,7.5 Hz, 1H), 6.75 (s, 1H), 6.73 (d, J=7.7 Hz, 1H), 6.42 (s, 1H), 5.22(ABq, 2H), 4.89 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.07-2.93 (m, 2H) ¹³CNMR (75 MHz, CDCl₃) δ178.0, 164.6, 161.6, 161.1, 157.4, 142.2, 132.9,128.4, 123.7, 123.2, 120.5, 119.7, 119.7, 119.4, 108.7, 93.0, 80.5,72.2, 57.7, 45.7, 29.0; MS (ES+) m/z 372.3 (M+1).

EXAMPLE 9.6 Synthesis of1-(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and4-(chloromethyl)pyrimidine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 158-160° C.; ¹H NMR (300MHz, CDCl₃) δ 9.16 (s, 1H), 8.68 (d, J=4.1 Hz, 1H), 7.30-7.15 (m, 3H),7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.55 (s, 1H), 6.39(s, 1H), 5.04 (ABq, 2H), 4.84 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H),3.06-2.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 164.1, 161.8, 161.2,158.6, 157.3, 141.5, 132.4, 128.7, 124.0, 123.7, 119.9, 119.8, 118.9,108.8, 93.1, 80.5, 72.3, 57.6, 44.9, 28.9; MS (ES+) m/z 372.3 (M+1).

EXAMPLE 9.7 Synthesis of1′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(chloromethyl)pyrazine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (27%) as a colorless solid: mp 143-144° C.; ¹H NMR (300MHz, CDCl₃) δ8.64 (br s, 1H), 8.58-8.59 (m, 2H), 7.24-7.17 (m, 2H),7.09-7.02 (m, 1H), 6.91-6.86 (m, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 5.14(ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H), 3.10-2.91 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.9, 161.9, 161.3, 151.4, 144.2, 143.9, 143.8, 141.6,132.7, 128.8, 124.0, 123.8, 120.0, 119.9, 119.0, 109.1, 93.2, 80.6,72.4, 57.8, 43.8, 29.0; MS (ES+) m/z 372.3 (M+1).

EXAMPLE 9.8 Synthesis of1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-7-fluorobenzofuran to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (83%) as a colorless solid: mp 192-193° C.; ¹H NMR (300MHz, CDCl₃) δ7.31-7.24 (m, 2H), 7.22-6.96 (m, 5H), 6.77-6.74 (m, 1H),6.56 (s, 1H), 6.43 (s, 1H), 5.31-5.23 (m, 1H), 5.03-4.95 (m, 2H),4.75-4.68 (m, 1H), 4.59-4.49 (m, 2H), 3.10-2.91 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ177.6, 161.8, 161.2, 152.8, 147.8 (d, J_(C-F)=249.7 Hz),141.9 (d, J_(C-F)=11.3 Hz), 141.4, 132.7, 131.6 (d, J_(C-F)=3.2 Hz),128.8, 123.9, 123.7, 123.6, 120.1 (d, J_(C-F)=5.2 Hz), 119.0, 116.6 (d,J_(C-F)=3.9 Hz), 110.8 (d, J_(C-F)=16.1 Hz), 109.0, 105.6 (d,J_(C-F)=2.1 Hz), 93.2, 80.4, 72.4, 57.7, 37.5, 29.0; MS (ES+) m/z 428.3(M+1).

EXAMPLE 9.9 Synthesis of1′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and3-(chloromethyl)pyridazine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (13%) as a colorless solid: mp 81-82° C.; ¹H NMR (300 MHz,CDCl₃) δ9.18-9.14 (m, 1H), 7.58-7.44 (m, 2H), 7.28-7.15 (m, 2H),7.12-7.02 (m, 2H), 6.47 (s, 1H), 6.43 (s, 1H), 5.39-5.22 (m, 2H), 4.84(ABq, 2H), 4.60-4.49 (m, 2H), 3.10-2.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ178.1, 161.9, 161.4, 158.4, 151.1, 141.6, 132.4, 129.0, 127.3, 126.0,123.9, 123.8, 120.0, 119.9, 118.8, 109.6, 93.3, 80.6, 72.4, 57.8, 44.6,29.0; MS (ES+) m/z 372.3 (M+1).

EXAMPLE 9.10 Synthesis of1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and5-chloromethyl-2-oxazolidinone to replace2-(bromomethyl)-5-(trifluoromethyl)furan,[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (32%) as a colorless solid: mp 197-198° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.58 (s, 1H), 7.37-7.29 (m, 1H), 7.26-7.20 (m, 1H),7.19-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.49-6.39 (m, 2H), 4.98-4.75 (m,2H), 4.74-4.66 (m, 1H), 4.54-4.45 (m, 2H), 4.15-3.84 (m, 2H), 3.67-3.56(m, 1H), 3.31-3.23 (m, 1H), 3.02-2.90 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.9, 177.6, 161.2, 160.6, 160.5, 158.3, 142.6 (2C), 132.2, 132.0,128.7, 128.6, 123.5, 123.4, 123.0, 120.6, 120.5, 119.9, 119.0, 118.9,109.7, 109.6, 92.5, 92.4, 79.8, 73.3, 73.2, 72.1, 56.8, 43.1, 42.7,42.6, 28.4; MS (ES+) m/z 379.3 (M+1).

EXAMPLE 9.11 Synthesis of1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and1-(benzyloxy)-3-(bromomethyl)benzene to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 66-68° C.; ¹H NMR (300 MHz,CDCl₃) δ7.43-7.14 (m, 8H), 7.06-6.99 (m, 1H), 6.97-6.87 (m, 3H),6.81-6.75 (m, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.10-5.00 (m, 3H),4.85-4.75 (m, 1H), 4.84 (ABq, 2H), 4.56-4.47 (m, 2H), 2.98-2.88 (m, 2H);¹³C NMR (75 MHz, CDCl₃) δ 177.9, 161.8, 161.3, 159.2, 142.1, 137.4,136.6, 132.7, 129.9, 128.7, 128.6, 128.0, 127.5, 123.8, 123.4, 120.2,119.9 (2C), 118.8, 114.0, 113.9, 109.3, 93.2, 80.5, 72.3, 70.0, 57.7,44.0, 29.0; MS (ES+) m/z 476.1 (M+1).

EXAMPLE 9.12 Synthesis of1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)-1-methyl-1H-benzo[d]imidazole to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 244-246° C.; ¹H NMR (300MHz, CDCl₃) δ7.95-7.86 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.49-7.40 (m,2H), 7.32 (dd, J=7.6, 7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.07 (dd,J=7.6, 7.6 Hz, 1H), 6.52-6.36 (m, 2H), 5.51 (ABq, 2H), 4.81 (ABq, 2H),4.55 (t, J=8.6 Hz, 2H), 3.92 (s, 3H), 2.99 (t, J=8.6 Hz, 2H); MS (ES+)m/z 424.1 (M+1).

EXAMPLE 9.13 Synthesis of1′-(2H-benzotriazol-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(chloromethyl)-2H-benzo[d][1,2,3]triazo to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-(2H-benzotriazol-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 102-105° C.; ¹H NMR (300MHz, CDCl₃) δ8.14-7.96 (m, 1H), 7.89-7.80 (m, 1H), 7.53-7.44 (m, 2H),7.42-7.34 (m, 1H), 7.33-7.26 (m, 1H), 7.17-7.10 (m, 1H), 7.10-7.02 (m,1H), 6.58 (ABq, 2H), 6.41 (s, 1H), 6.19 (s, 1H), 4.77 (ABq, 2H), 4.51(t, J=8.6 Hz, 2H), 2.89 (t, J=8.6 Hz, 2H); MS (ES+) m/z 411.1 (M+1).

EXAMPLE 9.14 Synthesis of methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, andmethyl 2-(bromomethyl)benzoate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoatewas obtained (79%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.04(dd, J=7.7, 1.3 Hz, 1H), 7.43 (ddd, J=7.5, 7.5, 1.5 Hz, 1H), 7.38-7.29(m, 1H), 7.22-7.11 (m, 3H), 7.07-6.99 (m, 1H), 6.70 (d, J=7.7 Hz, 1H),6.55 (s, 1H), 6.43 (s, 1H), 5.52-5.34 (m, 2H), 5.00 (d, J=8.9 Hz, 1H),4.74 (d, J=8.9 Hz, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 3.08-2.94(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.2, 167.5, 161.8, 161.4, 142.3,137.5, 132.8, 132.7, 131.4, 129.1, 128.8, 128.6, 128.0, 127.4, 126.5,123.9, 123.5, 120.2, 120.0, 119.0, 109.4, 93.3, 80.8, 72.4, 65.9, 57.9,52.3, 42.4, 29.1, 15.3; MS (ES+) m/z 427.9 (M+1).

EXAMPLE 9.15 Synthesis of methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, andmethyl 3-(bromomethyl)benzoate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoatewas obtained (93%) as a colorless solid: mp 97-98° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ8.04 (s, 1H), 8.02-7.96 (m, 1H),7.58-7.52 (m, 1H), 7.49-7.42 (m, 1H), 7.25-7.17 (m, 2H), 7.09-7.00 (m,1H), 6.78 (d, J=7.5 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.16 (d, J=15.7Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.7 Hz, 1H), 4.74 (d, J=9.0Hz, 1H), 4.60-4.52 (m, 2H), 3.93 (s, 3H), 3.13-2.96 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ178.1, 166.7, 162.0, 161.4, 141.9, 136.3, 132.8, 131.9,130.9, 129.3, 129.2, 128.9, 128.4, 124.1, 123.7, 120.2, 120.1, 119.1,109.2, 93.4, 80.7, 72.5, 57.9, 52.3, 43.9, 29.2; MS (ES+) m/z 428.1(M+1).

EXAMPLE 9.16 Synthesis of methyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, andmethyl 4-(bromomethyl)benzoate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, methyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoatewas obtained (95%) as a colorless solid: mp 136-140° C.; ¹H NMR (300MHz, CDCl₃) δ8.01 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.17 (d,J=7.4 Hz, 2H), 7.02 (dd, J=7.4, 7.4 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H),6.48 (s, 1H), 6.44 (s, 1H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.54 (t,J=8.6 Hz, 2H), 3.89 (s, 3H), 3.06-2.92 (m, 2H); MS (ES+) m/z 428.1(M+1).

EXAMPLE 9.17 Synthesis of1′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, andbenzyl 3-bromopropyl ether to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (89%) as a colorless solid: mp 112-113° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.27 (m, 6H), 7.14 (d,J=6.0 Hz, 1H), 7.06-6.95 (m, 2H), 6.41-6.39 (m, 2H), 4.63 (AB, 2H),4.54-4.48 (m, 4H), 3.94-3.80 (m, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.95 (t,J=9.0 Hz, 2H), 2.07-1.99 (m, 2H); MS (ES+) m/z 428.1 (M+1).

EXAMPLE 9.18 Synthesis of5′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (60%) as a colorless solid: mp 167-169° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

7.06-6.85 (m, 3H), 6.47 (s, 1H), 6.39 (s, 1H), 4.76 (ABq, 2H), 4.52 (t,J=9.0 Hz, 2H), 4.28-4.20 (m, 1H), 3.89-3.69 (m, 4H), 2.98-2.95 (m, 2H),2.10-1.63 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)

178.0, 161.9, 161.2, 157.9, 138.7, 134.3, 120.0, 118.8, 115.1, 114.8,111.7, 111.4, 110.5, 93.3, 80.5, 72.4, 68.2, 58.0, 44.8, 29.0, 28.9,25.7; MS (ES+) m/z 382.1 (M+1).

EXAMPLE 9.19 Synthesis of6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,6′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: mp 137-139° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.08-7.03 (m, 1H), 6.88-6.83 (m, 1H), 6.73-6.66 (m, 1H), 6.46 (s, 1H),6.38 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 4.25-4.20 (m, 1H),3.96-3.60 (m, 4H), 2.98 (t, J=9.0 Hz, 2H), 2.08-1.86 (m, 3H), 1.73-1.64(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 161.9, 161.2, 128.1, 124.7,120.0, 118.8, 109.5, 109.2, 98.8, 98.4, 93.2, 80.6, 72.4, 68.3, 57.3,44.8, 29.2, 28.9, 25.7; MS (ES+) m/z 382.0 (M+1).

EXAMPLE 9.20 Synthesis of1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and1-bromo-2-(2-methoxyethoxy)ethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: mp 90-91° C.; ¹H NMR (300 MHz,CDCl₃) δ7.32-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.05-6.97 (m, 2H), 6.46(s, 1H), 6.21 (s, 1H), 4.73 (ABq, 2H), 4.19-4.12 (m, 2H), 4.12-4.05 (m,2H), 4.05-3.96 (m, 1H), 3.94-3.83 (m, 1H), 3.64-3.57 (m, 2H), 3.51-3.44(m, 2H), 3.32 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 155.2, 144.5,142.5, 138.3, 132.3, 128.7, 123.7, 123.2, 121.2, 111.6, 109.2, 99.3,80.0, 71.9, 70.4, 68.2, 64.5, 63.9, 59.0, 58.0, 402; MS (ES+) m/z 397.9(M+1).

EXAMPLE 9.21 Synthesis of2-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,2-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-onewas obtained (38%) as a colorless solid: mp 249-250° C. (ethyl acetate);¹H NMR (300 MHz, DMSO-d₆) δ8.63-8.59 (m, 1H), 7.95 (d, J=8.6 Hz, 1H),7.85-7.70 (m, 2H), 7.38-7.31 (m, 1H), 7.27-7.1 (m, 3H), 7.02-6.95 (m,1H), 6.85 (d, J=7.8 Hz, 1H), 5.31 (d, J=16.9 Hz, 1H), 4.96-4.84 (m, 3H),2.67 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.4, 170.2, 160.2, 155.7,149.3, 148.5, 142.3, 137.0, 131.9, 128.8, 128.1, 123.4, 123.1, 122.7,120.7, 119.5, 109.3, 108.4, 81.0, 57.4, 45.6, 20.1; MS (ES+) m/z 400.0(M+1).

EXAMPLE 9.22 Synthesis of1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations usingmethylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and5-chloro-2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride to replace2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 177-178° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.63 (dd, J=8.6, 1.1 Hz, 1H), 7.47(d, J=7.9 Hz, 1H), 7.29-7.23 (m, 1H), 7.08-6.92 (m, 4H), 5.42 (d, J=15.4Hz, 1H), 5.08-5.00 (m, 1H), 4.85-4.74 (m, 2H), 3.67 (s, 3H), 2.51 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ176.8, 169.6, 160.5, 149.1, 142.1, 141.8,132.1, 129.1, 124.6, 123.7, 123.3, 122.5, 119.6, 119.3, 110.7, 108.7,81.3, 60.5, 58.2, 38.4, 31.2, 20.2; MS (ES+) m/z 437.0 (M+1), 439.0(M+1).

EXAMPLE 9.23 Synthesis of4-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using4-methyl-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indole]-2′,3(1′H,4H)-dioneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and(R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,4-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dionewas obtained (11%) as a colorless solid: ¹H NMR (300 MHz, (CD₃)₂CO)δ7.35-7.30 (m, 1H), 7.23-7.13 (m, 2H), 7.08-6.99 (m, 1H), 6.75 (s, 1H),6.35 (d, J=10.1 Hz, 1H), 4.92-4.87 (m, 1H), 4.74 (d, J=9.2 Hz, 1H),4.45-4.44 (m, 2H), 4.31-4.20 (m, 1H), 3.97-3.62 (m, 4H), 3.33 (s, 3H),1.95-1.66 (m, 4H); ¹³C NMR (75 MHz, (CD₃)₂CO) δ178.8, 178.7, 166.1,158.4 (2C), 145.3, 145.1, 141.5, 133.9, 133.7, 133.2, 130.6, 130.5,125.6, 125.3 (2C), 125.1 (2C), 124.6, 124.3, 112.9, 112.7, 111.6, 111.5,99.2, 99.1, 82.0, 81.8 (2C), 79.6, 78.2, 77.9, 75.7, 69.4, 69.3, 69.1,59.6, 59.5, 46.0, 45.8, 30.7, 30.4, 29.8, 29.4, 27.2, 27.1; MS (ES+) m/z406.9 (M+1).

EXAMPLE 9.24 Synthesis of3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(bromomethyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (24%) as a colorless solid: mp 142-143° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ8.58 (d, J=6.0 Hz, 1H),7.75-7.69 (m, 1H), 7.75-7.69 (m, 1H), 7.52-7.46 (m, 2H), 7.23-7.11 (m,3H), 7.01-6.96 (m, 2H), 6.85 (d, J=6.0 Hz, 1H), 5.45-4.89 (m, 4H), 2.45(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ176.1, 164.0, 158.2, 155.3, 154.9,149.3, 142.0, 137.3, 130.4, 129.4, 123.7, 123.6, 123.0, 122.7, 121.5,117.9, 109.9, 108.9, 108.0, 81.4, 56.4, 46.4, 9.8; MS (ES+) m/z 383.9(M+1).

EXAMPLE 9.25 Synthesis of3-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 3-(bromomethyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: mp 176-177° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

8.71 (d, J=3.0 Hz, 1H), 8.56-8.54 (m, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.46(d, J=9.0 Hz, 1H), 7.35-7.30 (m, 1H), 7.23-7.11 (m, 2H), 7.01-6.96 (m,2H), 6.77 (d, J=9.0 Hz, 1H), 5.28-4.81 (m, 4H), 2.44 (s, 3H); ¹³C NMR(75 MHz, CDCl₃)

176.2, 164.0, 158.1, 155.0, 154.9, 149.4, 148.8, 141.5, 135.1, 131.0,130.4, 129.4, 124.0, 123.9, 123.8, 123.1, 117.9, 109.4, 108.9, 108.0,81.3, 56.3, 41.9, 9.8; MS (ES+) m/z 383.9 (M+1).

EXAMPLE 9.26 Synthesis of3-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using (R)-(tetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (50%) as a colorless solid: mp 134-135° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.43 (d, J=9.0 Hz, 1H),7.32-6.93 (m, 5H), 4.94 (ABq, 2H), 4.36-4.28 (m, 1H), 4.06-3.73 (m, 4H),2.42 (s, 3H), 2.14-1.77 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 176.8, 176.3,164.0, 158.2, 154.8, 143.2, 142.6, 130.4, 129.3, 123.5, 123.3, 122.9,117.9, 110.5, 109.6, 109.1, 107.9, 81.4, 81.3, 77.8, 77.5, 68.4, 68.3,56.3, 56.2, 44.9, 44.6, 29.4, 28.5, 26.1, 25.6, 9.8; MS (ES+) m/z 377.0(M+1).

EXAMPLE 9.27 Synthesis of5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and4-bromomethyltetrahydropyrane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (55%) as a colorless solid: mp 199-201° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.32-7.27 (m, 1H), 7.14-7.12 (m, 1H), 7.05-7.00 (m, 2H), 6.91-6.89 (m,1H), 6.75 (s, 1H), 6.41 (s, 1H), 4.71 (ABq, 2H), 4.12-3.95 (m, 2H),3.75-3.54 (m, 2H), 3.39-3.28 (m, 2H), 2.19-2.02 (m, 7H), 1.62-1.28 (m,4H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 159.1, 142.8, 138.5, 132.6, 129.4,128.7, 125.8, 124.0, 123.7, 123.2, 111.4, 108.5, 79.9, 67.4, 58.0, 46.0,33.9, 30.8, 20.3, 19.3; MS (ES+) m/z 364.3 (M+1).

EXAMPLE 9.28 Synthesis of5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (76%) as a colorless solid: mp 165-168° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ8.67 (d, J=6.0 Hz, 1H),8.12-8.06 (m, 1H), 7.59-7.55 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.20 (m,1H), 7.03-6.98 (m, 2H), 6.76 (s, 1H), 6.55 (s, 1H), 5.18 (s, 2H), 4.74(ABq, 2H), 2.13 (s, 3H), 2.01 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.5,159.1, 154.0, 146.7, 142.6, 141.5, 138.3, 132.6, 129.1, 126.7, 124.5,124.4, 124.1, 123.7, 123.5, 111.3, 109.7, 79.5, 57.8, 43.7, 20.2, 19.2;MS (ES+) m/z 357.2 (M+1).

EXAMPLE 9.29 Synthesis of5-fluoro-6-methoxy-1-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and4-(bromomethyl)tetrahydropyran to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30(ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.16-7.00 (m, 2H), 6.89 (d, J=7.8 Hz,1H), 6.59 (d, J=6.8 Hz, 1H), 6.38 (d, J=10.0 Hz, 1H), 4.90 (d, J=9.0 Hz,1H), 4.65 (d, J=9.0 Hz, 1H), 4.02-3.92 (m, 2H), 3.85 (s, 3H), 3.76-3.51(m, 2H), 3.35 (t, J=11.5 Hz, 2H), 2.18-2.00 (m, 1H), 1.65-1.37 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.4, 157.3 (d, J=1.7 Hz), 149.3, 149.1,149.0, 146.1, 142.7, 131.9, 129.1, 123.7 (d, J=49.0 Hz), 118.9 (d, J=6.4Hz), 110.3 (d, J=21.7 Hz), 96.4, 80.7, 67.41, 67.39, 57.9, 56.4, 46.1,33.9, 30.8, 30.7; MS (ES+) m/z 384.2 (M+1).

EXAMPLE 9.30 Synthesis of5-fluoro-6-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,5-fluoro-6-methoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 45-47° C.; ¹H NMR (300 MHz,CDCl₃) δ7.32 (dd, J=7.8, 1.2 Hz, 1H), 7.20-6.98 (m, 3H), 6.77-6.73 (m,1H), 6.61 (d, J=6.6 Hz, 1H), 6.44-6.38 (m, 2H), 5.05 (d, J=16.2 Hz, 1H),4.96 (d, J=9.3 Hz, 1H), 4.90 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.3 Hz, 1H),3.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.8, 157.1 (d, J=1.8 Hz),151.8 (d, J=1.4 Hz), 149.2, 149.1 (d, J=12.3 Hz), 146.1, 141.5 (q,J=42.6 Hz), 141.3, 131.6, 129.2, 124.0, 123.9, 118.7 (d, J=265.4 Hz),118.6 (d, J=7.3 Hz), 112.6 (q, J=2.8 Hz), 110.3 (d, J=21.6 Hz), 109.1(d, J=25.1 Hz), 96.3, 80.4, 57.9 (d, J=1.3 Hz), 56.4, 36.9; MS (ES+) m/z433.9 (M+1).

EXAMPLE 9.31 Synthesis of5,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and3-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,5,6-difluoro-1-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (57%) as a colorless solid: mp 175-177° C.; ¹H NMR (300MHz, CD₃OD) δ 8.98 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.67 (d, J=8.4 Hz,1H), 8.12 (dd, J=8.1, 6.0 Hz, 1H), 7.37 (ddd, J=7.5, 7.5, 1.2 Hz, 1H),7.26 (d, J=6.9 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H),6.93 (dd, J=10.5, 6.3 Hz, 1H), 6.76 (dd, J=9.6, 7.8 Hz, 1H), 5.27 (s,1H), 5.26 (s, 1H), 5.00 (d, J=9.6 Hz, 1H), 4.83 (d, J=9.6 Hz, 1H); MS(ES+) m/z 365.2 (M+1).

EXAMPLE 9.32 Synthesis of5,6-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,5,6-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (64%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.34(dd, J=7.5 Hz, 1H), 7.21-6.99 (m, 3H), 6.82-6.74 (m, 2H), 6.53-6.39 (m,2H), 5.07 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.3 Hz, 1H), 4.90 (d, J=15.9Hz, 1H), 4.73 (d, J=9.3 Hz, 1H); MS (ES+) m/z 422 (M+1).

EXAMPLE 9.33 Synthesis of6-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,6-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′-indolin]-2′-onewas obtained (67%) as a colorless solid: mp 122-123° C.; ¹H NMR (300MHz, CDCl₃) δ 8.56 (s, 1H), 7.63 (dd, J=7.8, 7.8 Hz, 1H), 7.32-7.09 (m,3H), 7.0 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.65 (d, J=7.8Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=7.8, 2.1 Hz, 1H), 5.18 (d,J=15.9 Hz, 1H), 4.98 (d, J=15.9 Hz, 1H), 5.00 (d, J=8.7 Hz, 1H), 4.72(d, J=8.7 Hz, 1H), 3.74 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 162.1,161.5, 155.5, 149.4, 142.1, 137.0, 132.3, 128.7, 123.7, 123.6, 123.4,122.7, 121.5, 120.8, 109.4, 107.5, 96.5, 80.4, 57.6, 55.5, 46.0; MS(ES+) m/z 359.4 (M+1).

EXAMPLE 9.34 Synthesis of6-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and3-(bromomethyl)pyridine hydrobromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan,6-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (63%) as a colorless solid: mp 164-165° C.; ¹H NMR (300MHz, CDCl₃) δ 8.56 (s, 1H), 8.55 (d, J=3.9 Hz, 1H), 7.67 (d, J=7.8 Hz,1H), 7.33-7.13 (m, 3H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz,1H), 6.61-6.51 (m, 2H), 6.37 (dd, J=8.4, 2.1 Hz, 1H), 5.08 (d, J=15.6Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.72 (d, J=9.0Hz, 1H), 3.76 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 162.1, 161.6,149.3, 148.8, 141.5, 135.2, 132.4, 131.5, 128.8, 124.0, 123.8, 123.7,123.4, 120.5, 108.8, 107.5, 96.6, 80.4, 57.5, 55.5, 41.6; MS (ES+) m/z359.4 (M+1).

EXAMPLE 9.35 Synthesis of6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and4-(bromomethyl)tetrahydro-2H-pyran to replace2-(bromomethyl)-5-(trifluoromethyl)furan,6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (84%) as a colorless foam; ¹H NMR (300 MHz, CDCl₃) δ 7.31(dd, J=7.5, 1.2 Hz, 1H), 7.15 (dd, J=7.5, 1.2 Hz, 1H), 7.04 (dd, J=7.5Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.4Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d,J=9.0 Hz, 1H), 4.03-3.94 (m, 2H), 3.77 (s, 3H), 3.80-3.30 (m, 4H),2.21-2.05 (m, 1H), 1.74-1.38 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8,162.1, 161.5, 142.7, 132.6, 128.7, 123.9, 123.3, 123.2, 120.8, 108.5,107.5, 96.6, 80.6, 67.4, 67.3, 57.5, 55.5, 46.0, 33.9, 30.8, 30.7; MS(ES+) m/z 366.4 (M+1).

EXAMPLE 9.36 Synthesis of6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and2-(bromomethyl)tetrahydro-2H-pyran to replace2-(bromomethyl)-5-(trifluoromethyl)furan,6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless foam; ¹H NMR (300 MHz, CDCl₃) δ 7.28(dd, J=7.5, 7.5 Hz, 1H), 7.20-6.98 (m, 3H), 6.66-6.49 (m, 2H), 6.41-6.33(m, 1H), 4.99-4.91 (m, 1H), 4.74-4.66 (m, 1H), 4.02-3.31 (m, 8H),1.92-1.19 (m, 6H); MS (ES+) m/z 366.4 (M+1).

EXAMPLE 9.37 Synthesis of1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(2.0 g, 6.8 mmol) in dry N,N-dimethylformamide (45 mL) was added sodiumhydride (60% in mineral oil, 0.35 g, 8.8 mmol) at ambient temperature.The mixture was stirred at ambient temperature for 1 h and4-benzyloxybenzyl chloride (2.2 g, 9.4 mmol) was added in one portion,followed by potassium iodide (0.06 g, 0.34 mmol). The mixture wasstirred at ambient temperature for 16 h and diluted with water (200 mL)and ethyl acetate (200 mL). The layers were separated and the aqueouslayer was extracted with ethyl acetate (2×100 mL). The combined organiclayers were washed with brine (150 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 25% to 35% gradient of ethylacetate in hexanes to afford1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(2.49 g, 75%) as a colorless solid: mp 87-89° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.45-7.24 (m, 7H), 7.24-7.12 (m, 2H), 7.05-6.92 (m, 3H),6.84-6.79 (m, 1H), 6.51 (s, 1H), 6.22 (s, 1H), 5.06-4.90 (m, 4H),4.82-4.62 (m, 2H), 4.24-4.08 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4,158.4, 155.2, 144.6, 142.1, 138.3, 136.8, 132.3, 128.7 (2C), 128.6,128.0 (2C), 127.5, 123.8, 123.3, 121.0, 115.2, 111.5, 109.3, 99.4, 80.2,70.0, 64.5, 63.9, 58.0, 43.6; MS (ES+) m/z 492.0 (M+1).

EXAMPLE 9.38 Synthesis of1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.37 and makingnon-critical variations using5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one toreplace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (77%) as a colorless solid: mp 169-170° C.; ¹H NMR (300MHz, CDCl₃) δ 7.45-7.13 (m, 9H), 7.05-6.91 (m, 3H), 6.86-6.79 (m, 1H),6.46 (s, 1H), 6.43 (s, 1H), 5.06-4.94 (m, 4H), 4.83-4.75 (m, 1H),4.73-4.66 (m, 1H), 4.59-4.50 (m, 2H), 3.09-2.89 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ 177.9, 161.8, 161.3, 158.4, 142.1, 136.8, 132.8, 128.8,128.6 (2C), 128.2, 128.0, 127.4, 123.8, 123.3, 120.3, 119.9, 118.9,115.1, 109.2, 93.2, 80.6, 72.4, 70.0, 57.7, 43.6, 29.0; MS (ES+) m/z476.0 (M+1).

EXAMPLE 9.39 Synthesis of(8S)-1′-[4-(Benzyloxy)Benzyl]-2,3-Dihydrospiro[Furo[2,3-g][1,4]Benzodioxine-8,3′-Indol]-2′(1′H)-One

Following the procedure described in EXAMPLE 9 and making non-criticalvariations using(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and4-benzyloxybenzyl chloride to replace2-(bromomethyl)-5-(trifluoromethyl)furan,(8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 151-153° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.45-7.23 (m, 8H), 7.18-7.14 (m, 1H), 7.05-6.97 (m, 4H),6.53 (s, 1H), 6.06 (s, 1H), 5.07 (s, 2H), 4.86 (ABq, J=27.9, 15.6 Hz,2H), 4.73 (ABq, J=39.9, 9.3 Hz, 2H), 4.22-4.07 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.6, 157.7, 154.6, 144.1, 142.1, 137.8, 136.9, 131.7,128.7, 128.6, 128.4, 128.3, 127.8, 127.6, 123.5, 122.9, 121.2, 114.9,110.8, 109.4, 98.8, 79.4, 69.1, 64.1, 63.5, 57.2, 42.4; MS (ES+) m/z491.8 (M+1).

EXAMPLE 9.40 Synthesis of tert-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, andtert-butyl [5-(bromomethyl)pyridin-2-yl]carbamate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, tert-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamatewas obtained (74%) as a colorless solid: mp 238-239° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.81 (s, 1H), 8.30-8.27 (m, 1H), 7.79-7.73 (m, 1H),7.73-7.66 (m, 1H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.99 (m,2H), 6.52 (s, 1H), 6.06 (s, 1H), 4.89 (ABq, J=22.9, 15.5 Hz, 2H), 4.74(ABq, J=44.4, 9.3 Hz, 2H), 4.23-4.05 (m, 4H), 1.45 (s, 9H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.7, 154.6, 152.6, 151.8, 146.9, 144.1, 141.8, 137.8,137.2, 131.6, 128.7, 126.2, 123.6, 123.1, 121.1, 112.2, 110.8, 109.3,98.8, 79.5, 79.3, 64.1, 63.5, 57.2, 27.9; MS (ES+) m/z 502.1 (M+1).

EXAMPLE 9.41 Synthesis of3-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(trifluoromethyl)benzyl bromide toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (60%): mp 192-194° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.73-7.70 (m, 1H), 7.66-7.57 (m, 2H), 7.50-7.48 (m, 1H),7.41-7.36 (m, 1H), 7.22-7.14 (m, 2H), 7.05-6.98 (m, 2H), 6.68-6.64 (m,1H), 5.54-4.90 (m, 4H), 2.47 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.5,164.1, 158.1, 155.0, 141.8, 133.3, 132.8, 130.4, 129.5, 127.7, 127.5,127.4, 127.3, 126.3, 126.1, 123.8, 123.1, 117.9, 109.6, 108.9, 108.0,81.5, 56.4, 40.9, 9.8; MS (ES+) m/z 450.8 (M+1).

EXAMPLE 9.42 Synthesis of3-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using2-(chloromethyl)-3-(trifluoromethyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (87%): mp 221-222° C. (ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆) δ 8.66-8.64 (m, 1H), 8.21-8.18 (m, 1H), 7.75-7.72 (m, 1H),7.54-7.49 (m, 1H), 7.29-7.20 (m, 2H), 7.10-7.07 (m, 1H), 7.02-6.97 (m,2H), 5.27 (s, 2H), 4.96 (ABq, 2H), 2.41 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.7, 164.4, 158.0, 155.7, 155.6, 153.1, 152.7, 143.7,135.4, 135.3, 130.0, 129.7, 126.1, 124.5, 124.3, 123.5, 123.3, 123.1,122.5, 117.9, 109.9, 108.9, 108.4, 81.7, 56.0, 42.8, 9.8; MS (ES+) m/z451.8 (M+1).

EXAMPLE 9.43 Synthesis of1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using benzyl 3-bromopropyl ether to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (94%): mp 37-38° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.33-7.23 (m, 6H), 7.14-7.12 (m, 1H), 7.02-6.94 (m, 2H),6.47 (d, J=0.9 Hz, 1H), 6.18 (d, J=0.9 Hz, 1H), 4.70 (ABq, 2H), 4.47 (s,1H), 4.18-4.08 (m, 4H), 3.96-3.78 (m, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.01(d, J=6.6 Hz, 2H); MS (ES+) m/z 443.9 (M+1).

EXAMPLE 9.44 Synthesis of ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using ethyl bromoacetate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetatewas obtained (90%): mp 58-59° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.29-7.23 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.02 (m, 1H),6.77-6.74 (m, 1H), 6.47 (s, 1H), 6.34 (s, 1H), 4.89-4.39 (m, 4H),4.25-4.15 (m, 4H), 4.11-4.08 (m, 2H), 1.26 (t, J=9.0 Hz, 3H); MS (ES+)m/z 381.8 (M+1).

EXAMPLE 9.45 Synthesis of1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl}methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (98%): mp 55-57° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.30-6.99 (m, 4H), 6.47-6.20 (m, 2H), 4.88-4.84 (m, 1H),4.63-4.59 (m, 1H), 4.48-4.40 (m, 1H), 4.17-3.77 (m, 8H), 1.35-1.28 (m,6H); MS (ES+) m/z 410.1 (M+1).

EXAMPLE 9.46 Synthesis of6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using iodomethane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (62%): mp 207-208° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.27-7.20 (m, 3H), 7.10-6.99 (m, 2H), 6.90-6.83 (m, 4H),6.56 (s, 1H), 5.07-4.74 (m, 4H), 3.90 (s, 3H), 3.78 (s, 3H); MS (ES+)m/z 412.9 (M+1).

EXAMPLE 9.47 Synthesis of6-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, and6-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (80%): mp 187-189° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 8.57-8.55 (m, 1H), 7.70-7.64 (m, 1H), 7.27-7.20 (m, 3H),7.12-7.00 (m, 3H), 6.91-6.89 (m, 1H), 6.55 (s, 1H), 4.97 (ABq, 2H), 3.90(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.7, 165.8, 164.1, 154.9, 149.6,142.3, 137.1, 131.2, 129.4, 128.8, 123.7, 123.6, 122.9, 122.0, 121.7,116.7, 109.8, 94.6, 81.2, 56.9, 56.3, 45.9; MS (ES+) m/z 383.8 (M+1).

EXAMPLE 9.48 Synthesis of6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, and6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (55%): mp 108-109° C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.71-7.66 (m, 1H), 7.29-7.20 (m, 3H), 7.15-7.03 (m, 3H), 6.93-6.90 (m,1H), 6.79-6.76 (m, 1H), 5.26-4.85 (m, 4H); MS (ES+) m/z 371.9 (M+1).

EXAMPLE 9.49 Synthesis of6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using (R)-(tetrahydrofuran-2-yl)methyl4-methylbenzenesulfonate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (34%): ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.27 (m, 1H),7.12-7.06 (m, 3H), 7.01-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.94 (ABq, 2H),4.31-4.21 (m, 1H), 3.91-3.72 (m, 4H), 2.12-1.84 (m, 4H); MS (ES+) m/z364.9 (M+1).

EXAMPLE 9.50 Synthesis of6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(trifluoromethyl)benzyl bromide toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, and6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (55%): mp 193-195° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.76-7.73 (m, 1H), 7.53-7.39 (m, 2H), 7.27-7.22 (m, 1H),7.17-7.07 (m, 3H), 7.01-6.99 (m, 1H), 6.82-6.79 (m, 1H), 6.70-6.67 (m,1H), 5.27-5.09 (m, 3H), 4.90-4.87 (m, 1H); MS (ES+) m/z 419.0 (M−19).

EXAMPLE 9.51 Synthesis of6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using2-(chloromethyl)-3-(trifluoromethyl)pyridine to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (67%): mp 209-211° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, DMSO-d₆) δ 8.65 (d, J=6.0 Hz, 1H), 8.23 (d, J=6.0 Hz, 1H),7.58-7.54 (m, 1H), 7.42-7.40 (m, 1H), 7.31-7.23 (m, 3H), 7.06-7.01 (m,1H), 6.93-6.91 (m, 1H), 5.21 (s, 2H), 5.03 (s, 2H); MS (ES+) m/z 440.2(M+1).

EXAMPLE 9.52 Synthesis of4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 1-iodopentane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.20-7.15 (m, 2H), 6.87-6.83 (m, 1H), 6.45 (s, 1H), 6.16 (s, 1H), 4.89(ABq, 2H), 4.20-4.11 (m, 4H), 3.85-3.59 (m, 2H), 1.72-1.67 (m, 2H),1.38-1.25 (m, 4H), 0.92-0.85 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 117.0,156.4, 144.7, 144.5, 137.9, 130.13, 130.10, 126.9, 119.9, 118.1, 111.0,107.5, 98.9, 76.8, 64.4, 63.8, 59.3, 40.5, 28.9, 27.0, 22.3, 13.9; MS(ES+) m/z 443.9 (M+1), 445.9 (M+1).

EXAMPLE 9.53 Synthesis of methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using methyl 3-bromomethylbenzoate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoatewas obtained (99%) as a colorless solid: mp 89-97° C. (ethylacetate/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.98-7.95 (m, 2H),7.51-7.42 (m, 2H), 7.19-7.14 (m, 2H), 7.03-7.01 (m, 1H), 6.73-6.70 (m,1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.19-5.13 (m, 1H), 4.95-4.92 (m, 1H),4.84-4.79 (m, 1H), 4.67-4.64 (m, 1H), 4.19-4.11 (m, 4H), 3.90 (s, 3H)¹³C NMR (75 MHz, CDCl₃) δ 177.6, 166.7, 153.3, 144.7, 141.7, 138.4,136.1, 132.3, 131.7, 130.8, 129.2, 128.9, 128.1, 124.0, 123.6, 120.9,111.6, 109.2, 99.4, 80.2, 64.5, 63.9, 58.1, 52.3, 43.8, 29.7; MS (ES+)m/z 443.8 (M+1).

EXAMPLE 9.54 Synthesis of1′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 1-bromo-2-(2-methoxyethoxy)ethane toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (98%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ7.45-7.42 (m, 1H), 7.30-7.27 (m, 1H), 7.14-7.07 (m, 2H), 7.01-6.94 (m,2H), 5.09-5.06 (m, 1H), 4.85-4.82 (m, 1H), 4.08-3.98 (m, 2H), 3.84-3.80(m, 2H), 3.68-3.65 (m, 2H), 3.51-3.49 (m, 2H), 3.34 (s, 3H), 2.42 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 163.9, 154.8, 142.8, 130.4, 129.2,123.5, 123.3, 122.8, 117.9, 109.8, 107.9, 81.2, 72.0, 70.7, 68.6, 59.0,56.3, 40.8, 30.9, 9.8; MS (ES+) m/z 394.8 (M+1).

EXAMPLE 9.55 Synthesis of3-methyl-1′-(3-methylbutyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 1-bromo-3-methylbutane to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-(3-methylbutyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 135-138° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ 7.45-7.42 (m, 1H), 7.33-7.28 (m, 1H), 7.11-7.09(m, 1H), 7.01-6.94 (m, 3H), 5.07 (d, J=9.0 Hz, 1H), 4.82 (d, J=9.0 Hz,1H), 3.94-3.87 (m, 1H), 3.77-3.70 (m, 1H), 2.43 (s, 3H), 1.77-1.63 (m,3H), 1.01-0.98 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 175.7, 163.9, 158.3,154.8, 142.5, 130.8, 129.3, 123.7, 123.1, 122.8, 117.9, 109.2, 108.9,107.9, 81.2, 56.3, 39.1, 36.0, 26.0, 22.6, 22.4, 9.8; MS (ES+) m/z 362.8(M+1).

EXAMPLE 9.56 Synthesis of3-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(chloromethyl)pyrazine (Newkome, G. R.et al., Synthesis, (1984) 8:676) to replace2-(bromomethyl)-5-(trifluoromethyl)furan,3-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (20%) as a colorless solid: mp 170-173° C.(methanol/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.63-8.47(m, 2H), 7.48-7.45 (m, 1H), 7.21-6.91 (m, 5H), 5.34-5.29 (m, 1H),5.16-5.06 (m, 2H), 4.90-4.87 (m, 1H), 2.44 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.2, 163.9, 158.1, 154.9, 151.0, 144.1, 141.7, 130.4, 129.4,123.9, 123.1, 118.0, 109.6, 108.9, 107.9, 81.2, 56.4, 44.3, 9.8; MS(ES+) m/z 384.7 (M+1).

EXAMPLE 9.57 Synthesis of1′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 9 and makingnon-critical variations using 2-(chloromethyl)-3-fluoropyridine toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan,1′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (52%) as a colorless solid: mp 167-169° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ 8.38-8.36 (m, 1H), 7.47-7.37 (m, 2H),7.27-7.18 (m, 3H), 7.10-7.08 (m, 1H), 6.99-6.94 (m, 2H), 5.29-5.14 (m,3H), 4.88-4.85 (m, 1H), 2.44 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.0,164.1, 158.4, 156.3, 154.8, 145.3, 143.0, 142.4, 130.3, 129.2, 124.4,123.6, 123.5, 123.3, 122.9, 117.9, 109.7, 108.9, 107.9, 81.6, 56.4,41.3, 9.8; MS (ES+) m/z 401.8 (M+1).

EXAMPLE 9.58 Synthesis of methyl2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using methyl2-(chloromethyl)oxazole-4-carboxylate to replace2-(bromomethyl)-5-(trifluoromethyl)furan, methyl2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylatewas obtained (80%) as a colorless solid: mp 148-152° C.(dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 8.23 (s, 1H), 7.48-7.45 (m,1H), 7.30-7.27 (m, 1H), 7.13-7.11 (m, 1H), 7.06-6.95 (m, 3H), 5.20 (s,2H), 5.14-5.11 (m, 1H), 4.88-4.85 (m, 1H), 3.91 (s, 3H), 2.43 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 175.8, 163.9, 161.2, 159.0, 158.2, 154.9,145.3, 141.1, 133.5, 130.1, 129.6, 124.1, 123.2, 118.0, 109.3, 108.7,107.9, 81.2, 56.3, 52.3, 37.5, 30.9, 9.8; MS (ES+) m/z 431.8 (M+1).

EXAMPLE 9.59 Synthesis of methyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate

To a solution of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(3.50 g, 11.9 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C., wasadded sodium hydride (60% w/w dispersion in mineral oil, 0.72 g, 17.9mmol). The solution was stirred at 0° C. for 0.5 h and methyl4-(bromomethyl)benzoate (3.00 g, 13.1 mmol) was added. The solution wasstirred at ambient temperature for 16 h, further sodium hydride (60% w/wdispersion in mineral oil, 0.30 g, 7.5 mmol) and methyl4-(bromomethyl)benzoate (0.50 g, 2.2 mmol) were added and the mixturewas stirred for 1 h, filtered and concentrated in vacuo. The residue waspurified by column chromatography and eluted with a 25% to 50% gradientof ethyl acetate in hexanes to afford methyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate(4.51 g, 86%) as a colorless solid: mp 167-169° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=8.4 Hz, 2H), 7.37(d, J=8.4 Hz, 2H), 7.15 (d, J=7.4 Hz, 2H), 7.03-6.96 (m, 1H), 6.73-6.68(m, 1H), 6.48 (s, 1H), 6.22 (s, 1H), 5.10 (d, J=15.9 Hz, 1H), 4.92 (d,J=8.9 Hz, 1H), 4.84 (d, J=16.0 Hz, 1H), 4.65 (d, J=8.9 Hz, 1H),4.19-4.04 (m, 4H), 3.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 166.6,155.3, 144.7, 141.8, 140.9, 138.4, 132.2, 130.3, 129.8, 128.9, 127.3,124.0, 123.6, 120.9, 111.5, 109.2, 99.5, 80.1, 64.5, 63.9, 58.1, 52.2,43.9; MS (ES+) m/z 443.9 (M+1).

EXAMPLE 9.60 Synthesis of1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of sodium hydride (60% w/w dispersion in mineral oil,0.48 g, 12 mmol) in N,N-dimethylformamide (10 mL) at 0° C. was added2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-41H)-one (2.95g, 10 mmol). The reaction mixture was stirred for 30 min and4-benzyl-2-(chloromethyl)morpholine (2.71 g, 12 mmol) and potassiumiodide (0.10 g, 0.60 mmol) were added. The reaction mixture was heatedat 100° C. for 16 h, allowed to cool to ambient temperature andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with ethyl acetate/hexanes (3/7) to afford1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.75 g, 74%) as a colorless solid: mp 88-100° C.; ¹H NMR (mixture ofdiasteroisomers, 300 MHz, CDCl₃) δ7.35-7.20 (m, 6H), 7.16-7.11 (m, 1H),7.07-7.00 (m, 2H), 6.48 (s, 1H), 6.25 (s, 0.5H), 6.20 (s, 0.5H),4.90-4.80 (m, 1H), 4.64-4.57 (m, 1H), 4.22-4.08 (m, 4H), 3.98-3.40 (m,7H), 2.87-2.56 (m, 2H), 2.23-1.98 (m, 2H); MS (ES+) m/z 485.0 (M+1).

EXAMPLE 9.61 Synthesis of(8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.60 and makingnon-critical variations using (S)-4-benzyl-2-(chloromethyl)morpholine(Toshiya, M. et al., Heterocycles (1994), 38(5):1033-1040) to replace4-benzyl-2-(chloromethyl)morpholine, and(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (99%): MS (ES+) m/z 485.0 (M+1).

EXAMPLE 9.62 Synthesis of1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 4-bromobenzyl bromide to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (54%) as a pale yellow oil: ¹H NMR (300 MHz, CDCl₃) δ7.51(s, 1H), 7.48 (s, 1H), 7.23-7.04 (m, 5H), 6.82-6.77 (m, 2H), 6.50 (dd,J=8.9, 8.9 Hz, 1H), 5.03-4.96 (m, 2H), 4.84-4.72 (m, 2H); MS (ES+) m/z442.1 (M+1), 444.1 (M+1).

EXAMPLE 9.63 Synthesis of5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 1-bromo-3-methylbutane to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,5,6-difluoro-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (96%) as a pale yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.34(t, J=7.7 Hz, 1H), 7.16-7.04 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.77 (dd,J=10.3, 6.3 Hz, 1H), 6.50 (t, J=8.5 Hz, 1H), 4.95 (d, J=9.1 Hz, 1H),4.70 (d, J=9.1 Hz, 1H), 3.88-3.67 (m, 2H), 1.72-1.60 (m, 3H), 1.01 (d,6.2 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ176.3, 156.6 (d, J_(C-F)=11.0 Hz),151.1 (dd, J_(C-F)=248.1, 14.5 Hz), 145.6 (dd, J_(C-F)=241.3, 14.0 Hz),142.3, 131.6, 129.2, 123.8, 123.3, 111.5 (d, J=20.5 Hz), 108.7, 99.9 (d,J=22.3 Hz), 80.7, 57.7, 38.8, 36.0, 26.0, 22.4, 22.3; MS (ES+) m/z 344.4(M+1).

EXAMPLE 9.64 Synthesis of5,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, and5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,5,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (29%) as a pale yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.58(d, J=4.1 Hz, 1H), 7.71 (ddd, J=9.4, 7.7, 1.7 Hz, 1H), 7.31-7.22 (m,3H), 7.15 (dd, J=7.4, 0.9 Hz, 1H), 7.05 (ddd, J=8.4, 7.5, 0.9 Hz, 1H),6.94 (d, J=7.8 Hz, 1H), 6.79 (dd, J=10.3, 6.3 Hz, 1H), 6.66 (dd, J=9.2,7.9 Hz, 1H), 5.23 (d, J=15.9 Hz, 1H), 5.06-4.96 (m, 2H), 4.77 (d, J=9.1Hz, 1H); MS (ES+) m/z 365.3 (M+1).

EXAMPLE 9.65 Synthesis of5,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using 4-(bromomethyl)tetrahydro-2H-pyran toreplace 2-(bromomethyl)-5-(trifluoromethyl)furan, and5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,5,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (32%) as a pale yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 7.34(ddd, J=9.1, 7.7, 1.5 Hz, 1H), 7.16-7.05 (m, 2H), 6.93 (d, J=7.9 Hz,1H), 6.78 (dd, J=10.3, 6.3 Hz, 1H), 6.49 (dd, J=9.1, 7.8 Hz, 1H), 4.95(d, J=9.0 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.00 (dd, J=11.6, 2.5 Hz,2H), 3.75-3.56 (m, 2H), 3.37 (ddd, J=14.0, 11.6, 2.3 Hz, 2H), 2.15-2.08(m, 1H), 1.62-1.41 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 176.8, 156.7 (d,J_(C-F)=10.9 Hz), 151.1 (dd, J_(C-F)=248.4, 14.5 Hz), 145.6 (dd,J_(C-F)=241.4, 14.0 Hz), 142.6, 131.3, 129.3, 124.0, 123.7 (dd,J_(C-F)=6.1, 3.1 Hz), 123.5, 111.5 (d, J_(C-F)=20.4 Hz), 108.8, 100.1(d, J_(C-F)=22.3 Hz), 80.9, 67.3, 57.7, 46.1, 33.8, 30.7; MS (ES+) m/z372.1 (M+1).

EXAMPLE 9.66 Synthesis of2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione

Following the procedure as described in EXAMPLE 9 and makingnon-critical variations using N-(3-bromopropyl)phthalimide to replace2-(bromomethyl)-5-(trifluoromethyl)furan, and5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dionewas obtained (39%) as a pale yellow solid: mp 214-217° C.; ¹H NMR (300MHz, CDCl₃) δ 7.84 (dd, J=5.6, 3.0 Hz, 2H), 7.72 (dd, J=5.5, 3.0 Hz,2H), 7.31-7.28 (m, 1H), 7.18 (dd, J=7.4, 0.8 Hz, 1H), 7.04 (ddd, J=8.4,7.5, 0.8 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.58 (s, 1H), 6.40 (s, 1H),4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H),3.98-3.89 (m, 1H), 3.85-3.75 (m, 3H), 3.01 (ddd, J=10.6, 8.4, 1.7 Hz,2H), 2.20-2.10 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 168.1, 161.7,161.2, 141.9, 134.0, 133.0, 131.9, 128.7, 124.0, 123.3, 123.2, 120.2,119.9, 118.9, 108.2, 93.1, 80.4, 72.4, 57.6, 38.0, 35.7, 29.0, 26.8; MS(ES+) m/z 466.9 (M+1).

EXAMPLE 9.67 Synthesis of1-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

To a solution of7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one (0.400g, 1.4 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodiumhydride (60% w/w dispersion in mineral oil, 0.086 g, 3.6 mmol) at 0° C.and the mixture was stirred for 20 minutes.5-(Benzyloxy)-2-(chloromethyl)pyridine (0.44 g, 1.9 mmol) was added andthe reaction mixture was stirred at ambient temperature for 19 h.Potassium iodide (−10 mg, catalytic amount) was added and the reactionmixture was stirred at 60° C. for 2 h, at ambient temperature for 43 h,at 60° C. for 7 h and at ambient temperature for 3 days. Saturatedaqueous ammonium chloride (7 mL) and water (30 mL) were added and themixture was extracted with ethyl acetate (3×10 mL). The combined organicextracts were washed with water (2×20 mL) and brine (20 mL), dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography and eluted with hexanes/ethyl acetate(3/2), followed by trituration in hexanes to afford1-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one(0.034 g, 5%) as a pale yellow solid: mp 209-212° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.36 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.50 (d, J=8.7Hz, 1H), 7.45-7.23 (m, 8H), 7.18 (d, J=7.5 Hz, 1H), 7.03 (t, J=7.5 Hz,1H), 6.92 (J=7.8 Hz, 1H), 5.39 (d, J=15.9 Hz, 1H), 5.27 (d, J=9.6 Hz,1H), 5.11 (s, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H); ¹³CNMR (75 MHz, CDCl₃) δ176.0, 163.0, 154.4, 148.3, 147.1, 144.9, 142.2,137.8, 136.0, 129.8, 129.7, 128.7, 128.3, 127.6, 123.7, 123.6, 122.4,122.3, 121.9, 119.3, 110.2, 107.0, 82.0, 70.4, 57.4, 46.0; MS (ES+) m/z477.2 (M+1).

EXAMPLE 9.68 Synthesis of ethyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate

Following the procedure as described in EXAMPLE 9.67 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one,and ethyl 4-(bromomethyl)benzoate to replace5-(benzyloxy)-2-(chloromethyl)pyridine, ethyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoatewas obtained (95%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.03(d, J=8.4 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.21-7.16 (m, 2H), 7.03 (t,J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.14(d, J=15.9 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H),4.67 (d, J=8.7 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 4.22-4.19 (m, 2H),4.15-4.12 (m, 2H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 458.1 (M+1).

EXAMPLE 9.69 Synthesis of2-[3-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione

Following the procedure as described in EXAMPLE 9.67 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3-indol]-2′(1′H)-one toreplace 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one,and N-(3-bromopropyl)phthalimide to replace5-(benzyloxy)-2-(chloromethyl)pyridine,2-[3-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dionewas obtained (92%) as a pale yellow solid: ¹H NMR (300 MHz, CDCl₃) δ7.85-7.82 (m, 2H), 7.74-7.69 (m, 2H), 7.29-7.24 (m, 1H), 7.15 (d, J=7.2Hz, 1H), 7.08-7.00 (m, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.29(s, 1H), 4.89 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.18-4.10 (m,4H), 3.94-3.77 (m, 4H), 2.19-2.10 (m, 2H).

EXAMPLE 9.70 Synthesis of(8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.27 g, 0.9 mmol) in dry N,N-dimethylformamide (15 mL) was added sodiumhydride (60% w/w dispersion in mineral oil, 0.054 g, 1.4 mmol) atambient temperature. The mixture was stirred at ambient temperature for15 minutes and 1-bromo-2-(2-methoxyethoxy)ethane (0.33 g, 1.8 mmol) wasadded in one portion. The mixture was stirred at 60° C. for 6 h andconcentrated in vacuo. Water (50 mL) was added to the residue and themixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo. The residue was purified by column chromatography and elutedwith 40% ethyl acetate in hexanes to afford(8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.31 g, 85%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.20(m, 1H), 7.15-7.08 (m, 1H), 7.05-6.96 (m, 2H), 6.46 (s, 1H), 6.21 (s,1H), 4.73 (ABq, 2H), 4.20-4.04 (m, 4H), 4.05-3.83 (m, 2H), 3.80-3.69 (m,2H), 3.64-3.56 (m, 2H), 3.51-3.44 (m, 2H), 3.32 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 177.5, 155.1, 144.5, 142.5, 138.2, 132.3, 128.6, 123.7,123.2, 121.2, 111.5, 109.2, 99.3, 80.0, 71.9, 70.4, 68.1, 64.5, 63.9,59.0, 57.9, 40.2; MS (ES+) m/z 397.9 (M+1).

EXAMPLE 9.71 Synthesis of6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-oneto replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-onewas obtained (37%): mp 156-158° C.; ¹H NMR (300 MHz, CDCl₃) δ8.77 (s,1H), 8.07 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.56 (s, 1H), 6.23(s, 1H), 4.83 (ABq, 2H), 4.23-4.04 (m, 6H), 3.85-3.77 (m, 2H), 3.67-3.61(m, 2H), 3.52-3.46 (m, 1H), 3.32 (s, 3H); MS (ES+) m/z 455.1 (M+1).

EXAMPLE 9.72 Synthesis of6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-oneto replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)pyridine hydrobromide to replace1-bromo-2-(2-methoxyethoxy)ethane,6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-onewas obtained (41%) as a colorless solid: mp 156-158° C.; ¹H NMR (300MHz, CDCl₃) δ8.75 (s, 1H), 8.60-8.53 (m, 1H), 7.98 (d, J=8.2 Hz, 1H),7.69-7.61 (m, 1H), 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.13 (d, J=8.2Hz, 1H), 6.56 (s, 1H), 6.30 (s, 1H), 5.17 (ABq, 2H), 4.87 (ABq, 2H),4.24-4.03 (m, 4H); MS (ES+) m/z 444.1 (M+1).

EXAMPLE 9.73 Synthesis of4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless solid: mp 158-160° C.; ¹H NMR (300MHz, DMSO-d₆) δ6.43 (s, 1H), 6.33 (d, J=4.2 Hz, 1H), 6.20 (s, 1H), 6.06(d, J=4.2 Hz, 1H), 4.70-4.46 (m, 2H), 4.19-3.99 (m, 4H), 3.79-3.72 (m,2H), 3.65-3.52 (m, 4H), 3.52-3.42 (m, 2H), 3.38-3.24 (m, 6H), 3.18-3.11(m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.8, 162.0, 156.7, 155.6, 155.5,144.7, 144.1, 137.6, 120.4, 110.9, 109.2, 98.8, 92.9, 89.2, 71.0, 70.4,68.3, 64.4, 63.9, 59.0, 56.9, 55.6, 55.5, 40.3; MS (ES+) m/z 458.1(M+1).

EXAMPLE 9.74 Synthesis of4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one,and 2-(bromomethyl)pyridine hydrobromide to replace1-bromo-2-(2-methoxyethoxy)ethane,4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (78%) as a colorless solid: mp 187-188° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.59-8.34 (m, 1H), 7.86-7.66 (m, 1H), 7.44-7.19 (m, 2H),6.51-6.32 (m, 1H), 6.32-6.14 (m, 3H), 5.17-4.80 (m, 2H), 4.79-4.50 (m,2H), 4.25-3.95 (m, 4H), 3.66 (s, 3H), 3.61 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ178.7, 162.0, 156.7, 155.8, 155.6, 149.4, 144.3, 144.2, 137.7,137.1, 122.7, 121.5, 120.3, 111.1, 108.9, 98.9, 93.1, 89.5, 64.5, 63.9,57.1, 55.6, 46.2; MS (ES+) m/z 447.1 (M+1).

EXAMPLE 9.75 Synthesis of6-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using6-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,6-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (94%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆)δ7.32-7.27 (m, 1H), 7.12 (d, J=7.2 Hz, 1H), 7.07-6.98 (m, 2H), 6.85 (d,J=8.7 Hz, 1H), 6.76 (dd, J=8.7, 2.6 Hz, 1H), 6.32 (d, J=2.6 Hz, 1H),4.78 (ABq, 2H), 4.08-3.88 (m, 4H), 3.82-3.74 (m, 2H), 3.68-3.59 (m, 4H),3.52-3.47 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H); MS (ES+) m/z 414.1 (M+1).

EXAMPLE 9.76 Synthesis of5-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 9.70 and makingnon-critical variations using5-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,5-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (80%) as a colorless oil: ¹H NMR (300 MHz, DMSO-d₆)δ7.31-7.27 (m, 1H), 7.15-7.10 (m, 1H), 7.06-6.99 (m, 2H), 6.63-6.58 (m,1H), 6.56-6.53 (m, 1H), 6.42-6.36 (m, 1H), 4.81 (ABq, 2H), 4.11-4.02 (m,2H), 3.83-3.76 (m, 2H), 3.75-3.70 (m, 2H), 3.69-3.54 (m, 4H), 3.52-3.45(m, 2H), 3.43 (s, 3H), 3.33 (s, 3H); MS (ES+) m/z 414.1 (M+1).

EXAMPLE 10 Synthesis of1-(pyridazin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred suspension of5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one (0.20 g,0.72 mmol) and pyridazin-4-ylmethanol (0.08 g, 0.72 mmol) in drytetrahydrofuran (5 mL) was added at 0° C. tributylphosphine (0.27 mL,1.1 mmol), followed by N,N,N′,N′-tetramethylazodicarboxamide (0.19 g,1.1 mmol). The mixture was stirred at 0° C. for 15 min and at ambienttemperature for 64 h. Saturated aqueous solution of ammonium chloride(10 mL) was added and the mixture was extracted with ethyl acetate(4×100 mL). The combined organic solution was washed with water (2×60mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The residue was purified by columnchromatography (hexanes/ethyl acetate from 1:1 to 1:3) to afford1-(pyridazin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.03 g, 11%): mp 187-189° C.; ¹H NMR (300 MHz, CDCl₃) δ 9.25-9.16 (m,2H), 7.44-7.39 (m, 1H), 7.29-7.21 (m, 2H), 7.14-7.07 (m, 1H), 6.74-6.69(m, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 5.00 (ABq, 2H), 4.85 (ABq, 2H),4.60-4.52 (m, 2H), 3.11-2.93 (m, 2H); ¹³C NMR (75 MHz, CD₃OD) δ178.1,162.1, 161.4, 151.3, 150.7, 141.0, 135.5, 132.5, 129.0, 124.7, 124.5,124.3, 120.2, 119.5, 118.7, 108.4, 93.4, 80.6, 72.4, 57.7, 41.0, 29.0;MS (ES+) m/z 372.3 (M+1);

EXAMPLE 11 Synthesis of1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of 2-bromothiazole-5-methanol (0.80 g, 4.12 mmol) in thionylchloride (10 mL) was refluxed for 3 h, and the mixture was evaporated todryness and dried in vacuo. The residue was re-dissolved in 2-butanone(15 mL), followed by addition of cesium carbonate (2.61 g, 8.0 mmol) andspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.12 g, 4.0mmol). The reaction mixture was refluxed for 16 h, then concentrated todryness in vacuo. The residue was taken up in ethyl acetate (200 mL),washed by water (50 mL) and brine (50 mL). The organic phase was driedover sodium sulfate, filtered, and the filtrate was concentrated todryness. The residue was purified by flash chromatography with 25% ethylacetate in hexanes to afford1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.70 g, 38%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.58 (s,1H), 7.30 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.09 (ddd,J=7.5, 7.5, 0.9 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.09 (s,1H), 5.90-5.86 (m, 2H), 5.16-5.08 (m, 1H), 4.97 (d, J=15.9 Hz, 1H), 4.92(d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H); MS (ES+) m/z 413.0 (M+1),415.0 (M+1).

EXAMPLE 11.1 Synthesis of1′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of1′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.10 g, 0.24 mmol) in N,N-dimethylformamide (5 mL) was added 2 Mdimethyl amine in tetrahydrofuran (2.0 mL, 4.0 mmol) under nitrogen in asealed tube. The reaction mixture was heated at 120° C. for 16 h. Thereaction was quenched with the water, then extracted with ethyl acetate(2×50 mL). The combined organic solution was dried over sodium sulfate,filtered, and the filtrate was concentrated to dryness. The residue waspurified by flash chromatography with 30% ethyl acetate in hexanes toafford1′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.08 g, 76%) as a colorless solid: mp 200-202° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.27 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.20 (s, 1H), 7.15 (d,J=7.5 Hz, 1H), 7.08-6.95 (m, 2H), 6.51 (s, 1H), 6.14 (s, 1H), 5.91-5.84(m, 2H), 5.05 (d, J=15.6 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.84 (d,J=15.6 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 3.06 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ177.2, 172.0, 156.1, 149.0, 142.5, 141.5, 139.1, 132.4, 129.1,124.1, 123.7, 119.7, 119.5, 109.2, 103.3, 101.6, 93.7, 80.5, 58.2, 40.4,37.2; MS (ES+) m/z 422.1 (M+1).

EXAMPLE 11.2 Synthesis of1′-[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.1 and makingnon-critical variations using morpholine to replace dimethyl amine,1′-[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 97-99° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.28 (dd, J=7.5, 7.5, Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=7.5 Hz,1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.51 (s, 1H),6.11 (s, 1H), 5.91-5.84 (m, 2H), 5.05 (d, J=15.6 Hz, 1H), 4.92 (d, J=9.0Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 3.78 (t, J=4.8Hz, 4H), 3.43 (t, J=4.8 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3, 172.3,156.1, 149.1, 142.5, 141.4, 138.6, 132.4, 129.1, 124.2, 123.8, 120.9,119.4, 109.1, 103.3, 101.7, 93.8, 80.5, 66.2, 58.2, 48.6, 37.0; MS (ES+)m/z 464.1 (M+1).

EXAMPLE 11.3 Synthesis of1′-[(2-piperidin-1-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.1 and makingnon-critical variations using piperidine to replace dimethyl amine,1′-[(2-piperidin-1-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (98%) as a colorless solid: mp 195-197° C.; ¹H NMR (300MHz, CDCl₃) δ7.27 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 7.17 (s, 1H), 7.16 (d,J=7.5 Hz, 1H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H),6.51 (s, 1H), 6.14 (s, 1H), 5.90-5.84 (m, 2H), 5.04 (d, J=15.6 Hz, 1H),4.92 (d, J=9.0 Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H),3.46-3.36 (m, 4H), 1.70-1.57 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ177.2,172.3, 156.1, 149.0, 142.5, 141.5, 138.6, 132.4, 129.1, 124.1, 123.7,119.5, 119.4, 109.2, 103.3, 101.6, 93.7, 80.5, 58.2, 49.8, 37.1, 25.1,24.1; MS (ES+) m/z 462.1 (M+1).

EXAMPLE 11.4 Synthesis of1′-[(2-methoxy-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.1 and makingnon-critical variations using sodium methoxide to replace dimethylamine,1′-[(2-methoxy-1,3-thiazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (19%) as a colorless solid: mp 164-166° C.; ¹H NMR (300MHz, CDCl₃) δ 7.28 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.20-7.13 (m, 2H),7.06 (dd, J=7.5, 7.5 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.51 (s, 1H), 6.11(s, 1H), 5.90-5.84 (m, 2H), 5.05 (d, J=15.6 Hz, 1H), 4.92 (d, J=9.0 Hz,1H), 4.85 (d, J=15.6 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.03 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ177.2, 175.7, 156.1, 149.1, 142.5, 141.3, 136.2,132.4, 129.1, 124.7, 124.3, 123.9, 119.3, 108.9, 103.2, 101.7, 93.8,80.5, 58.4, 58.2, 37.2; MS (ES+) m/z 409.1 (M+1).

EXAMPLE 11.5 Synthesis of1-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A solution of tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate(0.94 g, 1.98 mmol) and trifluoroacetic acid (2 mL) in dichloromethane(10 mL) was stirred at ambient temperature for 1.5 h. The reaction wasmade basic with 1 M sodium hydroxide solution (30 mL) and extracted withdichloromethane (3×25 mL). The combined organic solution was dried oversodium sulfate, filtered and concentrated under reduced pressure toafford1-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.73 g, 98%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.30 (dd,J=7.8, 7.5 Hz, 1H), 7.16 (d, J=6.9 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz,1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.41 (s, 1H), 4.91 (d, J=8.9Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.54 (t, J=8.6 Hz, 2H), 3.71 (dd,J=13.9, 7.5 Hz, 1H), 3.57 (dd, J=13.9, 7.1 Hz, 1H), 3.21-3.11 (m, 2H),2.99 (td, J=8.7, 2.7 Hz, 2H), 2.74 (br s, 1H), 2.67-2.56 (m, 2H),2.08-1.94 (m, 1H), 1.77-1.66 (m, 2H), 1.44-1.30 (m, 2H).

EXAMPLE 11.6 Synthesis of1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A solution of1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one(0.29 g, 0.77 mmol), acetone (0.10 mL, 1.4 mmol), sodiumcyanoborohydride (0.10 g, 1.51 mmol) and acetic acid (6 drops) inmethanol (4 mL), sealed in a well-stoppered round-bottomed flask, wasstirred at 60° C. for 16 h. The reaction was cooled, diluted withsaturated aqueous sodium bicarbonate (30 mL) and extracted withdichloromethane (3×25 mL). The organic solution was dried over sodiumsulfate, filtered and concentrated under reduced pressure. Purificationby flash column chromatography with dichloromethane/methanol (14:1)afforded1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.21 g, 64%) as a colorless foam: ¹H NMR (300 MHz, CD₃OD) δ 7.33 (ddd,J=7.8, 7.5, 0.9 Hz, 1H), 7.14-7.05 (m, 3H), 6.44 (s, 1H), 6.32 (s, 1H),4.81 (d, J=9.2 Hz, 1H), 4.65 (d, J=9.2 Hz, 1H), 4.99 (t, J=8.7 Hz, 2H),3.74 (dd, J=14.0, 7.2 Hz, 1H), 3.65 (dd, J=14.0, 7.1 Hz, 1H), 3.02-2.91(m, 4H), 2.77 (septet, J=6.6 Hz, 1H), 2.30-2.18 (m, 2H), 2.00-1.84 (m,1H), 1.81-1.71 (m, 2H), 1.50-1.34 (m, 2H), 1.08 (d, J=6.6 Hz, 6H); ¹³CNMR (75 MHz, CD₃OD) δ180.3, 163.2, 162.9, 144.1, 134.1, 123.0, 124.8,124.6, 121.6, 121.4, 120.0, 110.5, 93.7, 81.7, 73.5, 59.2, 56.2, 49.5,49.4, 46.6, 36.0, 30.7 (2C), 29.9, 18.3, 18.3; MS (ES+) m/z 419.2 (M+1).

EXAMPLE 11.7 Synthesis of1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

A solution of1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo-[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.21 g, 0.49 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.50 mL,2.0 mmol) in methanol (1.5 mL) was stirred at ambient temperature for 30min. The solvent was removed under reduced pressure, the residue wassuspended in ethyl acetate/hexanes and the resulting precipitate wascollected by filtration. The precipitate was dried to afford1-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.17 g, 76%) as a colorless powder: mp 167° C. (dec.)(hexanes); ¹H NMR (300 MHz, CD₃OD) δ7.36 (ddd, J=7.8, 7.2, 1.2 Hz, 1H),7.19-7.08 (m, 3H), 6.48 (s, 1H), 6.33 (s, 1H), 4.83 (d, J=9.3 Hz, 1H),4.67 (d, J=9.3 Hz, 1H), 4.51 (t, J=8.6 Hz, 2H), 3.80 (dd, J=14.3, 7.5Hz, 1H), 3.73 (dd, J=14.3, 7.1 Hz, 1H), 3.54-3.42 (m, 3H), 3.07-2.96 (m,4H), 2.31-2.16 (m, 1H), 2.09-1.98 (m, 2H), 1.76-1.60 (m, 2H), 1.35 (d,J=6.6 Hz, 6H); ¹³C NMR (75 MHz, CD₃OD) δ180.4, 163.3, 162.9, 143.8,134.0, 130.1, 124.9, 124.8, 121.5 (2C), 120.1, 110.4, 93.7, 81.8, 73.5,59.7, 59.3, 49.5, 45.8, 34.1, 29.9, 28.7, 28.67, 17.0; MS (ES+) m/z419.3 (M+1); Anal. Calcd. for C₂₆H₃₀N₂O₃.HCl.2H₂O: C, 63.60; H, 7.18; N,5.71. Found: C, 63.80; H, 6.83; N, 5.67.

EXAMPLE 11.8 Synthesis of1-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.37 g, 0.99 mmol), acetaldehyde (0.08 mL, 1.4 mmol) and sodiumtriacetoxyborohydride (0.32 g, 1.51 mmol) in 1,2-dichloroethane (4 mL)was stirred at ambient temperature for 17.5 h. The orange reactionmixture was diluted with saturated aqueous sodium bicarbonate (30 mL)and was extracted with dichloromethane (3×25 mL). The organic solutionwas dried over sodium sulfate, filtered and concentrated under reducedpressure. Purification by flash column chromatography withdichloromethane/methanol (19:1) afforded1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.32 g, 80%) as a yellow foam: ¹H NMR (300 MHz, CDCl₃) δ7.29 (ddd,J=7.8, 7.8, 1.4 Hz, 1H), 7.15 (dd, J=7.5, 0.9 Hz, 1H), 7.04 (ddd, J=7.5,7.5, 0.8 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.45 (s, 1H), 6.41 (s, 1H),4.90 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H),3.73 (dd, J=14.0, 7.4 Hz, 1H), 3.60 (dd, J=14.0, 7.1 Hz, 1H), 3.10-2.95(m, 4H), 2.52 (q, J=7.1 Hz, 2H), 2.14-1.87 (m, 3H), 1.83-1.72 (m, 2H),1.67-1.52 (m, 2H), 1.15 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)δ178.2, 161.9, 161.5, 143.0, 132.9, 128.9, 124.1, 123.4, 120.3, 120.0,118.9, 108.8, 93.4, 80.9, 72.5, 57.8, 52.6, 45.8, 34.5, 29.6, 29.5,29.2, 11.7; MS (ES+) m/z 405.2 (M+1).

EXAMPLE 11.9 Synthesis of1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

A solution of1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.17 g, 0.41 mmol) and hydrogen chloride (4.0 M in 1,4-dioxane, 0.40mL, 1.6 mmol) in methanol (1.0 mL) was stirred at ambient temperaturefor 35 min. The solvent was removed under reduced pressure, the residuewas suspended in ethyl acetate/hexanes and the precipitate was collectedby filtration and washed with hexanes. The precipitate was dried toafford1′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.18 g, 100%) as an off-white powder: mp 135° C. (dec.)(hexanes); ¹H NMR (300 MHz, CD₃OD) δ7.36 (dd, J=6.9, 6.6 Hz, 1H),7.20-7.07 (m, 3H), 6.49 (s, 1H), 6.32 (s, 1H), 4.83 (d, J=9.2 Hz, 1H),4.67 (d, J=9.2 Hz, 1H), 4.50 (t, J=8.3 Hz, 2H), 3.84-3.68 (m, 2H),3.65-3.54 (m, 2H), 3.21-3.10 (m, 2H), 3.02-2.87 (m, 4H), 2.31-2.16 (m,1H), 2.08-1.95 (m, 2H), 1.76-1.58 (m, 2H), 1.35 (t, J=6.2 Hz, 3H); ¹³CNMR (75 MHz, CD₃OD) δ180.4, 163.2, 162.9, 143.8, 133.9, 130.1, 124.9,124.8, 121.5 (2C), 120.1, 110.5, 93.7, 81.8, 73.5, 59.2, 53.4, 53.0,45.9, 34.0, 29.9, 28.7 (2C), 9.7; MS (ES+) m/z 405.2 (M+1).

EXAMPLE 11.10 Synthesis of1′-[(1-methylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.354 g, 0.94 mmol), formaldehyde solution (37% in water, 0.80 mL, 10.6mmol) and formic acid (0.80 mL, 21.2 mmol) in water (2 mL) was stirredat 80° C. for 14.5 h. The reaction was diluted with 1 M sodium hydroxide(25 mL) and extracted with dichloromethane (3×25 mL). The organicsolution was dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification by flash column chromatography withmethanol/dichloromethane/ammonium hydroxide (32:1:0.17, increased to19:1:0.2) afforded1-[(1-methylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.18 g, 48%) as a colorless solid: mp 155-158° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) δ7.30 (dd, J=7.8, 7.5 Hz, 1H), 7.16 (d, J=6.9 Hz, 1H),7.04 (dd, J=7.5, 7.2 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.41(s, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.6Hz, 2H), 3.72 (dd, J=14.0, 7.4 Hz, 1H), 3.58 (dd, J=14.0, 6.9 Hz, 1H),2.99 (td, J=8.3, 1.2 Hz, 2H), 2.91-2.82 (m, 2H), 2.27 (s, 3H), 1.97-1.80(m, 3H), 1.75-1.65 (m, 2H), 1.53-1.38 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ178.1, 161.9, 161.5, 143.0, 133.0, 128.8, 124.1, 123.3, 120.3, 120.0,118.9, 108.7, 93.3, 80.9, 72.5, 57.7, 55.3, 46.5, 46.1, 34.3, 30.3,29.2; MS (ES+) m/z 391.2 (M+1); Anal. Calcd. for C₂₄H₂₆N₂O₃: C, 73.82;H, 6.71; N, 7.17. Found: C, 73.46; H, 7.10; N, 7.22.

EXAMPLE 11.11 Synthesis of1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.5 and makingnon-critical variations using tert-butyl(2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylateto replace tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate,tetrahydrofuran to replace dichloromethane,1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (89%) as a pale yellow solid: mp 83-86° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) (diastereomers) δ7.29 (dd, J=7.8, 7.5 Hz, 1H), 7.16(d, J=7.5 Hz, 1H), 7.07-6.99 (m, 2H), 6.52, 6.46 (s, 1H), 6.40 (s, 1H),4.95, 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz,2H), 3.91-3.71 (m, 2H), 3.69-3.60 (m, 1H), 3.14-2.90 (m, 5H), 1.98-1.70(m, 3H), 1.66-1.51 (m, 1H); MS (ES+) m/z 363.1 (M+1).

EXAMPLE 11.12 Synthesis of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

To a solution of methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate(2.80 g, 6.5 mmol) in tetrahydrofuran (30 mL) and water (10 mL) wasadded lithium hydroxide monohydrate (0.82 g, 19 mmol). The reactionmixture was stirred at ambient temperature for 16 h. Most of thetetrahydrofuran was removed in vacuo and the resultant solution waswashed with diethyl ether (2×50 mL). The aqueous phase was renderedacidic to litmus by the addition of 1 M hydrochloric acid and extractedwith ethyl acetate (3×50 mL). The combined organic solution was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was triturated with diethyl ether (50 mL) and the solid wascollected by vacuum filtration, washed with diethyl ether (20 mL),air-dried and dried under high vacuum to afford3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (2.20 g, 81%) as a colorless solid: mp>250° C. (water); ¹H NMR (300MHz, DMSO-d₆) δ13.06 (br s, 1H), 7.89-7.82 (m, 2H), 7.66 (d, J=7.6 Hz,1H), 7.55-7.47 (m, 1H), 7.29-7.16 (m, 2H), 7.07-6.96 (m, 2H), 6.49 (s,1H), 6.42 (s, 1H), 5.17-4.72 (m, 4H), 4.55-4.45 (m, 2H), 3.06-2.88 (m,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.2, 167.1, 161.2, 160.7, 142.0,136.9, 132.2, 131.8, 131.2, 129.1, 128.8, 128.4, 127.3, 123.8, 123.2,120.5, 120.0, 118.9, 109.3, 92.5, 79.7, 72.1, 57.0, 42.5; MS (ES+) m/z414.0 (M+1).

EXAMPLE 11.13 Synthesis of1′-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A stirred solution ofN′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide(0.40 g, 0.94 mmol) and trifluoroacetic anhydride (0.4 mL) in pyridine(2 mL) was heated at 170° C. in a microwave reactor for 30 min. Thesolution was concentrated in vacuo to dryness, purified by flashchromatography with ethyl acetate in hexanes (20% to 40% gradient) toafford1′-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.34 g, 71%) as a colorless solid: mp 178-179° C.; ¹H NMR (300 MHz,CDCl₃) δ8.09 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.24-7.16 (m,2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.48 (s, 1H),6.42 (s, 1H), 5.15 (d, J=15.9 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.90 (d,J=15.9 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.54 (t, J=8.62 Hz, 2H),3.07-2.93 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ194.7, 178.0, 168.8, 162.0,161.4, 141.8, 140.4, 132.7, 128.8, 128.3, 128.1, 124.5, 124.1, 123.7,120.0, 118.8, 116.0 (q, J=273.8 Hz), 109.1, 93.4, 80.7, 72.4, 57.8,43.9, 29.1; MS (ES+) m/z 506.0 (M+1).

EXAMPLE 11.14 Synthesis of1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.13 and makingnon-critical variations using acetyl chloride to replace trifluoroaceticanhydride,1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 185-186° C.; ¹H NMR (300MHz, CDCl₃) δ8.03 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.25-7.14(m, 2H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.47 (s,1H), 6.42 (s, 1H), 5.13 (d, J=15.8 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.86(d, J=15.8 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 2H),3.10-2.89 (m, 2H), 2.63 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 176.7,168.0, 161.9, 161.4, 141.9, 139.0, 132.7, 128.8, 127.9 (2C), 126.4,124.0, 123.6, 120.1, 120.0, 118.8, 109.2, 93.3, 80.6, 72.4, 57.8, 43.9,29.1, 12.4; MS (ES+) m/z 451.9 (M+1).

EXAMPLE 11.15 Synthesis of1′-[(5-pyridin-4-ylfuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.22 g, 0.5 mmol), pyridin-4-ylboronic acid (0.09 g, 0.75 mmol),tetrakis(triphenylphosphine) palladium (0.06 g, 0.05 mmol) and sodiumcarbonate (1 mL of 2 M water solution, 2.0 mmol) inN,N-dimethylformamide (4 mL) was heated in microwave reactor at 150° C.for 15 min. The reaction mixture was subjected to column chromatographywith ethyl acetate/hexanes (1:1) to afford1′-[(5-pyridin-4-ylfuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.15 g, 66%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.55 (s,2H), 7.52-7.00 (m, 6H), 6.83 (d, J=3.4 Hz, 1H), 6.48 (d, J=3.4 Hz, 1H),6.40 (s, 1H), 6.38 (s, 1H), 5.00 (ABq, 2H), 4.81 (ABq, 2H), 4.52-4.44(m, 2H), 2.87 (t, J=8.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 161.8,161.2, 151.0, 150.8, 149.7, 141.6, 137.3, 132.6, 128.7, 124.0, 123.7,120.1, 119.9, 118.8, 117.7, 111.2, 110.0, 108.9, 93.2, 80.4, 72.3, 57.6,37.2, 28.9; MS (ES+) m/z 436.8 (M+1).

EXAMPLE 11.16 Synthesis of1′-(4-pyridin-3-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.15 and makingnon-critical variations using pyridin-3-ylboronic acid to replacepyridin-4-ylboronic acid, and1′-(4-bromobenzyl)-)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1′-(4-pyridin-3-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (42%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.73-8.69 (m, 1H), 8.49-8.44 (m, 1H), 7.95-7.88 (m, 1H), 7.59-6.79 (m,9H), 6.45 (s, 1H), 6.35 (s, 1H), 5.11-5.01 (m, 1H), 5.11-4.81 (m, 3H),4.67 (dd, J=9.1, 1.42 Hz, 1H), 4.48 (t, J=8.6 Hz, 2H), 3.05-2.86 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ 181.4, 164.7, 164.2, 150.4, 150.0, 144.8,139.7, 139.6, 138.9, 138.3, 135.4, 131.8, 131.1, 130.5, 127.1, 126.8,126.7, 123.0, 121.8, 112.3, 96.0, 83.4, 75.3, 60.8, 46.6, 31.8; MS (ES+)m/z 446.8 (M+1).

EXAMPLE 11.17 Synthesis of1′-[(2′-fluorobiphenyl-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.15 and makingnon-critical variations using 2-fluorophenylboronic acid to replacepyridin-4-ylboronic acid, and1-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace1′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-[(2′-fluorobiphenyl-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (34%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ8.72-7.91 (m, 12H), 7.61 (s, 1H), 7.54 (s, 1H), 6.11 (ABq, 2H), 5.97(ABq, 2H), 5.64 (t, J=8.6 Hz, 2H), 4.20-4.01 (m, 2H); ¹³C NMR (75 MHz,CDCl₃) δ177.9, 161.8, 161.3, 158.0, 142.1, 135.3 (2C), 135.2, 132.8,130.6 (2C), 129.5, 129.4, 129.2, 129.1, 128.7, 128.4, 128.3, 127.5,124.4 (2C), 123.9, 123.4, 120.2, 119.9, 118.9, 116.3, 116.0, 109.3,93.2, 80.6, 72.4, 57.7, 43.9, 29.0.

EXAMPLE 11.18 Synthesis of1′-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a stirred solution ofN′-hydroxy-3-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1-yl)propanimidamide(0.50 g, 1.4 mmol) and diisopropylamine (0.3 mL, 2.0 mmol) indichloromethane (20 mL) was added trifluoromethylacetic anhydride (0.3mL, 2.0 mmol). The solution was stirred at ambient temperature for 1 h,then partitioned with saturated solution of ammonium chloride in water(10 mL) and the aqueous layer was extracted with dichloromethane (2×25mL). The combined organic solution was dried over sodium sulfate,filtered and concentrated in vacuo to dryness. The residue was purifiedby flash chromatography with ethyl acetate in hexanes (15% to 50%gradient) to afford1-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.20 g, 33%) as a colorless solid: mp 45-48° C.; ¹H NMR (300 MHz,CDCl₃) δ7.27-7.20 (m, 1H), 7.14 (d, J=7.1 Hz, 1H), 7.03 (dd, J=7.5, 7.5Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.87-5.83(m, 2H), 4.74 (ABq, 2H), 4.27-4.05 (m, 2H), 3.28 (td, J=6.4, 1.5 Hz,2H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 168.8, 166.0 (q, J=44.5 Hz), 155.9,148.9, 142.4, 141.4, 132.4, 128.8, 124.3, 123.6, 119.1, 115.8 (q,J=273.9 Hz), 107.8, 103.3, 101.5, 93.5, 80.5, 58.1, 37.8, 24.2; MS (ES+)m/z 446.1 (M+1).

EXAMPLE 11.19 Synthesis of4′-chloro-1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a stirred solution of2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide(0.39 g, 1.0 mmol) and diisopropylamine (0.20 mL, 1.5 mmol) indichloromethane (20 mL) was added trifluoromethylacetic anhydride (0.21mL, 1.5 mmol). The solution was stirred for 2 h at ambient temperaturethen concentrated in vacuo and dissolved in ethyl acetate (50 mL). Theethyl acetate solution was washed with saturated solution of ammoniumchloride in water (2×25 mL), dried over sodium sulfate, filtered andconcentrated in vacuo to dryness. The residue was purified by flashchromatography with ethyl acetate in hexanes (15% to 50% gradient) toafford1′-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.13 g, 29%) as a colorless solid: mp 138-140° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.34 (dd, J=8.0, 8.0 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.07 (d,J=8.1 Hz, 1H), 6.67 (s, 1H), 6.27 (s, 1H), 5.30 (ABq, 2H), 4.81 (ABq,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 167.6, 165.8 (q, J=106.3 Hz),156.6, 149.1, 143.7, 142.0, 131.0, 130.3, 128.4, 124.3, 117.1, 116.0 (q,J=273.2 Hz), 109.0, 103.2, 102.0, 93.4, 77.3, 58.4, 36.1; MS (ES+) m/z466.0 (M+1).

EXAMPLE 11.20 Synthesis of4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A stirred solution of2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamide(0.24 g, 0.52 mmol) in pyridine (1 mL) was heated at 170° C. for 30 minin a microwave reactor. The solution was concentrated in vacuo todryness, purified by flash chromatography with ethyl acetate in hexanes(15% to 50% gradient) to afford4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.36 g, 16%) as a colorless solid: mp 180-182° C.; ¹H NMR (300 MHz,CDCl₃) δ7.19 (dd, J=8.1, 8.1 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.77 (d,J=7.8 Hz, 1H), 6.46 (s, 1H), 6.28 (s, 1H), 5.86 (d, J=1.2 Hz, 1H), 5.04(ABq, 2H), 4.94 (ABq, 2H), 2.20-2.10 (m, 1H). 1.26-1.12 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ182.9, 177.0, 165.4, 156.8, 149.2, 143.0, 142.1, 131.6,130.0, 128.4, 124.6, 116.5, 107.4, 103.0, 101.5, 93.2, 58.7, 36.1,10.57, 10.53, 7.8; MS (ES+) m/z 438.1 (M+1).

EXAMPLE 11.21 Synthesis of4′-chloro-1′-{1-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.19 and makingnon-critical variations using difluoromethylacetic anhydride to replacetrifluoromethylacetic anhydride,4′-chloro-1′-{1-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (35%) as a colorless solid: mp 179-182° C.; ¹H NMR (300.MHz, CDCl₃) δ7.25-7.17 (m, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.76 (d, J=7.6Hz, 1H), 6.76 (t, J=52.0 Hz, 1H), 6.47 (s, 1H), 6.24 (s, 1H), 5.86 (ABq,2H), 5.15 (ABq, 2H), 4.94 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.1,170.6 (t, J=30.2 Hz), 166.3, 156.8, 149.3, 142.6, 142.2, 131.9, 130.3,128.2, 124.9, 116.1, 107.1, 105.3 (t, J=244.5 Hz), 102.9, 101.6, 93.3,58.7, 35.8; MS (ES+) m/z 448.1 (M+1).

EXAMPLE 11.22 Synthesis of1-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.19 and makingnon-critical variations using difluoromethylacetic anhydride to replacetrifluoromethylacetic anhydride, andN′-hydroxy-2-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)acetimidamideto replace2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide,1′-{[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (67%) as a colorless solid: mp 137-139° C.; ¹H NMR (300MHz, CDCl₃) δ7.30-7.17 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.85 (d,J=7.8 Hz, 1H), 6.76 (t, J=52.0 Hz, 1H), 6.50 (s, 1H), 6.26 (s, 1H), 6.85(m, 2H), 5.16 (ABq, 2H), 4.82 (ABq, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.4,170.5, 166.5, 155.8, 149.0, 142.4, 140.8, 132.2, 129.1, 124.2, 124.1,119.2, 108.6, 105.4 (t, J=244.2 Hz), 103.3, 101.5, 93.6, 80.2, 58.2,35.6; MS (ES+) m/z 414.1 (M+1).

EXAMPLE 11.23 Synthesis of1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a stirred solution ofN′-hydroxy-2-(2′-oxo-6H-spiro[benzofuro[6,5-c][1,3]dioxole-7,3′-indoline]-1-yl)acetimidamide(0.20 g, 0.57 mmol) and diisopropylamine (0.40 mL, 2.9 mmol) indichloromethane (10 mL) was added trimethylacetic anhydride (0.2 mL, 1.1mmol). The solution was stirred at ambient temperature for 2 h thenconcentrated in vacuo to afford the intermediate2-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1-yl)-N′-(pivaloyloxy)acetimidamide.The crude residue was dissolved in pyridine (3 mL) and heated at 170° C.for 30 min in a microwave reactor. The solution was concentrated invacuo to dryness, purified by flash chromatography with ethyl acetate inhexane (15% to 50% gradient) to afford1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.16 g, 67%) as a colorless solid: mp 183-185° C.; ¹H NMR (300 MHz,CDCl₃) δ7.27-7.16 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.85 (d, J=7.5Hz, 1H), 6.48 (s, 1H), 6.35 (s, 1H), 5.84 (d, J=3.3 Hz, 2H), 5.05 (ABq,2H), 4.83 (ABq, 2H), 1.39 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ187.4,177.4, 165.5, 155.7, 148.9, 142.4, 141.2, 132.4, 128.9, 123.9, 123.8,119.7, 108.8, 103.5, 101.5, 93.5, 80.1, 58.3, 36.1, 33.7, 28.3; MS (ES+)m/z 420.2 (M+1).

EXAMPLE 11.24 Synthesis of1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.23 and makingnon-critical variations using cyclopropane carboxylic acid chloride toreplace trimethylacetic anhydride,1′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (20%) as a colorless solid: mp 136-137° C.; ¹H NMR (300MHz, CDCl₃) δ7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.05(dd, J=7.5, 7.5 Hz, 1H), 6.86 (d, J=7.5 Hz, 1H), 6.48 (s, 1H), 6.30 (s,1H), 5.84 (d, J=3.8 Hz, 2H), 5.00 (ABq, J=16.4 Hz, 2H), 4.82 (ABq, J=9.0Hz, 2H), 2.20-2.09 (m, 1H), 1.21-1.16 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)δ182.7, 177.3, 165.6, 155.7, 148.9, 142.4, 141.2, 132.3, 128.9, 123.9,123.8, 119.6, 108.9, 103.5, 101.5, 93.5, 80.2, 58.2, 35.8, 10.50, 10.46,7.8; MS (ES+) m/z 404.1 (M+1).

EXAMPLE 11.25 Synthesis of4′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.23 and makingnon-critical variations using isobutyryl chloride to replacetrimethylacetic anhydride, and2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamideto replaceN′-hydroxy-2-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)acetimidamide,4′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (26%) as a colorless solid: mp 165-167° C.; ¹H NMR (300MHz, CDCl₃) δ7.19 (dd, J=8.0, 8.0 Hz, 1H), 7.00 (dd, J=8.2, 0.8 Hz, 1H),6.77 (dd, J=7.8, 0.7 Hz, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 5.85 (ABq,2H), 5.04 (ABq, 2H), 4.95 (ABq, 2H), 3.17 (sep, J=7.0 Hz, 1H), 1.36 (d,J=7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ185.2, 177.1, 165.3, 156.7,149.2, 143.0, 142.1, 131.6, 130.1, 128.4, 124.6, 116.5, 107.3, 103.1,101.5, 93.2, 77.1, 58.8, 36.2, 27.5, 20.1, 20.0; MS (ES+) m/z 440.1(M+1).

EXAMPLE 11.26 Synthesis of1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A stirred solution ofN′-hydroxy-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethanimidamide(0.35 g, 1.0 mmol) and isobutyric anhydride (250 mL, 1.5 mmol) inpyridine (3 mL) was heated at 170° C. in a microwave reactor for 30 min.The solution was concentrated in vacuo to dryness, purified by flashchromatography with ethyl acetate in hexanes (15% to 50% gradient) toafford1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.26 g, 64%) as a colorless solid: mp 196-199° C.; ¹H NMR (300 MHz,CDCl₃) δ7.28-7.15 (m, 2H), 7.05 (dd, J=7.5 Hz, 1H), 6.86 (d, J=7.8 Hz,1H), 6.49 (s, 1H), 6.34 (s, 1H), 6.86-6.82 (m, 2H), 5.06 (ABq, 2H), 4.83(ABq, 2H), 3.18 (sep, J=7.0 Hz, 1H), 1.36 (d, J=7.0 Hz, 6H); ¹³C NMR (75MHz, CDCl₃) δ185.0, 177.4, 165.6, 155.7, 148.9, 142.4, 141.2, 132.3,128.9, 123.9, 123.8, 119.7, 108.9, 103.5, 101.5, 93.5, 80.1, 58.2, 36.0,27.5, 20.1, 20.0; MS (ES+) m/z 406.2 (M+1).

EXAMPLE 11.27 Synthesis of1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution ofN′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide(0.36 g, 0.84 mmol) in pyridine (3 mL) was added acetyl chloride (0.12mL, 1.68 mmol). The reaction was stirred in a microwave reactor (170°C., 200 watts, 200 psi) for 30 min. The mixture was concentrated invacuo. The residue was purified by column chromatography with ethylacetate in hexanes (25% to 40% gradient), and recrystallized from ethylacetate and diethylether to afford1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.27 g, 71%) as a colorless solid: mp 209-213° C.; ¹H NMR (300 MHz,CDCl₃) δ8.06-8.03 (m, 1H), 7.99-7.96 (m, 1H), 7.48-7.44 (m, 2H),7.19-7.12 (m, 2H), 7.03-6.98 (m, 1H), 6.77-6.74 (m, 1H), 6.58 (s, 1H),6.42 (s, 1H), 5.18 (d, J=15.8 Hz, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.85 (d,J=15.8 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.56-4.50 (m, 2H), 3.07-2.95 (m,2H), 2.63 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 176.7, 168.1, 161.9,161.3, 141.9, 136.6, 132.8, 129.9, 129.6, 128.8, 127.5, 126.9, 126.0,124.0, 123.6, 120.2, 120.1, 119.1, 109.2, 93.2, 80.6, 72.4, 57.8, 43.8,29.1, 12.4; MS (ES+) m/z 451.8 (M+1).

EXAMPLE 11.28 Synthesis of1′-{3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.27 and makingnon-critical variations using trifluoroacetic anhydride to replaceacetyl chloride,1′-{3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (71%) as a colorless solid: mp 182-188° C.; ¹H NMR (300MHz, CDCl₃) δ8.12-7.97 (m, 2H), 7.60-7.51 (m, 2H), 7.25-7.17 (m, 2H),7.06-7.00 (m, 1H), 6.76-6.72 (m, 1H), 6.57 (s, 1H), 6.42 (s, 1H), 5.22(d, J=15.9 Hz, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.86 (d, J=15.9 Hz, 1H),4.72 (d, J=9.0 Hz, 1H), 4.57-4.51 (m, 2H), 3.07-2.92 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ178.1, 168.8, 161.9, 161.4, 141.7, 137.1, 132.8, 131.1,129.9, 128.8, 127.3, 126.1, 125.6, 124.1, 123.7, 120.2, 120.1, 119.0,109.1, 93.3, 80.6, 72.5, 65.9, 57.8, 43.7, 29.0, 15.3; MS (ES+) m/z505.8 (M+1).

EXAMPLE 11.29 Synthesis of1′-[4(5-methyl-4H-1,2,4-triazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.40 g, 0.96 mmol) in 1,4-dioxane (15 mL) was addedN,N-dimethylacetamide dimethyl acetal (1.42 mL, 9.71 mmol). The reactionwas heated to reflux for 18 h, concentrated in vacuo. To the aboveresidue were added acetic acid (15 mL) and hydrazine monohydrate (0.15mL, 3.17 mmol). The reaction was stirred at 90° C. for 6 h, cooled toambient temperature, quenched with saturated sodium bicarbonate (15 mL),and extracted with chloroform. The combined organic solution was washedwith water and brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography with 5% methanol in ethyl acetate, andrecrystallized from dichloromethane and hexanes to afford1′-[4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1'H)-one(0.07 g, 16%) as a colorless solid: mp 169-180° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) δ10.72 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1Hz, 2H), 7.15 (d, J=7.5 Hz, 2H), 7.01 (t, J=7.5 Hz, 1H), 6.79 (d, J=7.7Hz, 1H), 6.45 (s, 1H), 6.40 (s, 1H), 5.19-4.09 (m, 4H), 4.53-4.47 (m,2H), 2.95-2.90 (m, 2H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.3,161.9, 161.4, 141.9, 136.9, 132.7, 128.8, 127.8, 126.9, 123.9, 123.6,120.0, 119.9, 118.8, 109.4, 93.2, 80.6, 72.4, 57.8, 44.0, 28.9, 11.7; MS(ES+) m/z 450.8 (M+1).

EXAMPLE 11.30 Synthesis of2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

Lithium hydroxide monohydrate (1.48 g, 35.2 mmol) was added to asolution of methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate(6.00 g, 14.2 mmol) in a mixed solvent (tetrahyrofuran/water=2/1 v/v,180 mL), and stirred at ambient temperature for 16 h. Most oftetrahydrofuran was removed under vacuum, and 150 mL water was added.The solution was extracted with 50 mL of mixed solvent (ethylacetate/hexanes: 1/3 v/v). The water layer was acidified with 1 N HClsolution until pH 2. After filtration and air dry,2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid was obtained (5.60 g, 96%) as a colorless solid: ¹H NMR (300 MHz,DMSO-d₆) δ13.2 (br s, 1H), 7.95 (dd, J=7.7, 1.2 Hz, 1H), 7.51 (ddd,J=7.5, 7.5, 1.2 Hz, 1H), 7.37 (dd, J=7.5, 7.5 Hz, 1H), 7.24-7.14 (m,2H), 7.12-6.96 (m, 2H), 6.81 (d, J=7.7 Hz, 1H), 6.58 (s, 1H), 6.40 (s,1H), 5.39-5.18 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.74 (d, J=8.9 Hz, 1H),4.47 (t, J=8.7 Hz, 2H), 3.95 (s, 3H), 2.95 (t, J=8.7 Hz, 2H); ¹³C NMR(75 MHz, DMSO-d₆) δ177.8, 168.7, 161.6, 161.2, 143.0, 137.6, 133.0,132.6, 131.5, 129.8, 129.2, 127.7, 126.4, 124.2, 123.6, 120.9, 120.4,119.7, 109.7, 92.9, 80.5, 72.6, 57.5, 42.5, 28.8; MS (ES+) m/z 414.0(M+1).

EXAMPLE 11.31 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

Following the procedure as described in EXAMPLE 11.30 and makingnon-critical variations using methyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoateto replace methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid was obtained (95%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ12.93 (s, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.22(dd, J=7.4 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.00 (dd, J=7.4 Hz, 1H),6.94 (d, J=7.4 Hz, 1H), 6.45 (s, 1H), 6.40 (s, 1H), 4.98 (ABq, 2H), 4.77(ABq, 2H), 4.47 (t, J=8.9 Hz, 2H), 3.01-2.85 (m, 2H); MS (ES+) m/z 414.1(M+1).

EXAMPLE 11.32 Synthesis of5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid

A mixture of methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate(1.38 g, 3.17 mmol) and lithium hydroxide (0.76 g, 31.7 mmol) intetrahydrofuran (10 mL) and water (10 mL) was stirred at 60° C. for 2 h.The reaction mixture was acidified with 1 M hydrochloric acid (50 mL)and extracted with dichloromethane (3×30 mL). The combined organicsolution was washed with brine (50 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure to afford5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid (1.36 g, quantitative) as a colorless solid: mp 192-195° C.(diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ8.40 (br s, 1H), 7.27 (dd,J=7.8, 7.8 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.06(dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.45 (d,J=3.3 Hz, 1H), 6.31 (s, 1H), 5.19 (d, J=16.5 Hz, 1H), 4.92 (d, J=9.3 Hz,1H), 4.87 (d, J=16.5 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.21-4.07 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.4, 162.8, 155.2, 154.4, 144.8, 143.7,141.3, 138.6, 132.3, 129.1, 124.2, 124.0, 121.1, 120.9, 111.8, 110.7,109.0, 99.5, 80.0, 64.7, 64.0, 58.2, 37.5; MS (ES+) m/z 419.9 (M+1).

EXAMPLE 11.33 Synthesis ofN,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide

A solution of5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid (0.42 g, 1.00 mmol), dimethylamine hydrochloride (0.17 g, 2.04mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(0.26 g, 1.35 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol)and 4-methylmorpholine (0.30 mL, 2.7 mmol) in N,N-dimethylformamide (10mL) was stirred at ambient temperature for 16 h. The solvent was removedunder reduced pressure, the residue was taken up into ethyl acetate (75mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL), water(50 mL) and brine (50 mL). The organic phase was further diluted withdichloromethane until all the material was in solution, then was driedover sodium sulfate, filtered and concentrated under reduced pressure.Purification by flash column chromatography withdichloromethane/methanol (29:1) affordedN,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide(0.34 g, 77%) as a colorless solid: mp 224-226° C. (diethylether/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ7.32 (dd, J=7.5, 7.5 Hz, 1H),7.22-7.14 (m, 2H), 7.05 (dd, J=7.8, 7.5 Hz, 1H), 6.96 (m, 1H), 6.62 (m,1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.06 (d, J=16.4 Hz, 1H), 4.97 (d,J=16.4 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H),4.22-4.14 (m, 2H), 4.14-4.06 (m, 2H), 3.05 (br s, 3H), 2.94 (br s, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ176.4, 158.9, 154.6, 150.8, 147.2, 144.2,141.8, 137.8, 131.6, 128.8, 123.6, 123.3, 121.2, 116.5, 111.0, 109.9,109.4, 98.8, 79.3, 64.2, 63.6, 57.2, 37.7, 36.7, 35.8; MS (ES+) m/z446.9 (M+1).

EXAMPLE 11.34 Synthesis of1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A suspension of1′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(2.70 g, 6.31 mmol) and 10% palladium on carbon (1.00 g, 0.94 mmol) inmethanol (50 mL) was hydrogenated for 20 h. The reaction mixture wasfiltered through a pad of celite. The filtrate was concentrated invacuo, and the residue was subjected to column chromatography with ethylacetate in hexanes (20% to 50% gradient) to afford1-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(2.07 g, 97%): mp 54-56° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃)

7.33-7.28 (m, 1H), 7.19-7.17 (m, 1H), 7.09-7.04 (m, 1H), 6.94 (d, J=9.0Hz, 1H), 6.45 (s, 1H), 6.41 (s, 1H), 4.77 (ABq, 2H), 4.53 (t, J=6.0 Hz,2H), 4.02-3.84 (m, 2H), 3.63-3.54 (m, 2H), 3.07-2.90 (m, 3H), 1.94-1.83(m, 2H); MS (ES+) m/z 338.1 (M+1).

EXAMPLE 11.35 Synthesis of2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbonitrile

To a stirred solution of4′-bromo-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.20 g, 0.45 mmol), potassium hexacyanoferrate(II) trihydrate (0.04 g,0.1 mmol) in N,N-dimethylacetamide (5 mL) was added palladium(II)acetate (0.01 g, 0.04 mmol) followed with the addition of sodiumcarbonate (0.10 g, 0.9 mmol). The mixture was stirred at 130° C. for 18h. The mixture was filtered through a pad of celite, and the filtratewas concentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexanes, 1/2) to afford2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbonitrile(0.03 g, 16%): ¹H NMR (300 MHz, CDCl₃) δ7.41-7.25 (m, 3H), 6.46-6.38 (m,2H), 4.98-4.88 (m, 2H), 4.53 (t, J=8.7 Hz, 2H), 4.28-4.15 (m, 1H),4.03-3.62 (m, 4H), 2.98 (t, J=8.7 Hz, 2H), 2.14-2.00 (m, 1H), 1.97-1.83(m, 2H), 1.74-1.59 (m, 1H); MS (ES+) m/z 389.0 (M+1).

EXAMPLE 11.36 Synthesis of2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde

To a stirred solution of4′-bromo-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.80 g, 1.8 mmol) in anhydrous tetrahydrofuran was addedtert-butyllithium (2.7 mL 1.7 M in pentane, 4.5 mmol) at −78° C. Themixture was stirred at −78° C. for 45 min, followed by the addition ofN,N-dimethylformamide (1.4 mL, 18.1 mmol). The mixture was kept at −78°C. for 30 min before quenched with saturated ammonium chloride solution.The mixture was extracted with ethyl acetate (3×30 mL). The combinedorganic solution was dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated in vacuo. The residue was subjected tocolumn chromatography (ethyl acetate/hexanes, 1/2) to afford2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde(0.19 g, 26%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.94 (s,1H), 7.56 (dd, J=7.8, 1.2 Hz, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H),7.39-7.33 (m, 1H), 6.42 (s, 1H), 6.41 (s, 1H), 4.98 (d, J=9.2 Hz, 1H),4.86 (d, J=9.2 Hz, 1H), 4.51 (t, J=8.7 Hz, 2H), 4.31-4.19 (m, 1H),4.05-3.66 (m, 4H), 3.04-2.85 (m, 2H), 2.14-2.00 (m, 1H), 1.97-1.83 (m,2H), 1.77-1.63 (m, 1H); MS (ES+) m/z 392.0 (M+1).

EXAMPLE 11.37 Synthesis of4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-4′-carbaldehyde(0.10 g, 0.26 mmol) and dimethylamine (0.19 mL, 0.38 mmol) indichloroethane was added sodium triacetoxyborohydride (0.10 g, 0.46mmol) at 0° C. The mixture was stirred at ambient temperature for 18 h,and quenched with water. The mixture was extracted with ethyl acetate(3×20 mL). The combined organic solution was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography (methanol/ethyl acetate,5/100) to afford4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.05 g, 46%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.29-7.20(m, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.98 (t, J=7.0 Hz, 1H), 6.45-6.39 (m,1H), 6.38 (s, 1H), 5.07 (dd, J=8.8, 2.1 Hz, 1H), 4.88 (d, J=8.8 Hz, 1H),4.52 (t, J=8.6 Hz, 1H), 4.33-4.21 (m, 1H), 3.98-3.62 (m, 4H), 3.33 (dd,J=13.2, 3.3 Hz, 1H), 3.03-2.88 (m, 2H), 2.80 (d, J=13.2 Hz, 1H),2.09-1.63 (m, 10H); MS (ES+) m/z 421.0 (M+1).

EXAMPLE 11.38 Synthesis of4′-(pyrrolidin-1-ylmethyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.37 and makingnon-critical variations using pyrrolidine to replace dimethylamine,4′-(pyrrolidin-1-ylmethyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (75%): ¹H NMR (300 MHz, CDCl₃) δ7.29-7.20 (m, 1H), 7.09 (d,J=7.9 Hz, 1H), 6.98 (dd, J=7.0, 7.0 Hz, 1H), 6.45-6.39 (m, 1H), 6.36 (s,1H), 5.10 (dd, J=8.8, 2.1 Hz, 1H), 4.87 (d, J=8.8 Hz, 1H), 4.51 (t,J=8.6 Hz, 1H), 4.32-4.20 (m, 1H), 3.98-3.62 (m, 4H), 3.58 (dd, J=13.2,3.3 Hz, 1H), 3.03-2.89 (m, 3H), 2.40-1.59 (m, 12H); MS (ES+) m/z 447.1(M+1).

EXAMPLE 11.39 Synthesis of4′-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.20 g, 0.45 mmol), benzophenone imine (0.11 mL, 0.68 mmol) andrac-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (0.10 g, 0.16 mmol) intoluene (5 mL) was added tris(dibenzylideneacetone) dipalladium(0) (0.05g, 0.05 mmol) followed by the addition of sodium tert-butoxide (0.09 g,0.9 mmol). The mixture was stirred at 90° C. for 18 h, filtered througha pad of celite. The filtrate was concentrated in vacuo, and theobtained residue was dissolved in tetrahydrofuran (15 mL). Hydrochloridesolution (2 mL of 2 M solution) was added to the above mixture. Themixture was stirred at ambient temperature for 3 h. The mixture wasneutralized with sodium bicarbonate solution, and extracted with ethylacetate (3×30 mL). The combined organic solution was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo. The residue was subjected to column chromatography (hexanes/ethylacetate, 1/2) to afford4′-amino-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.07 g, 46%) as a colorless solid: mp 190-192° C.; ¹H NMR (300 MHz,CDCl₃) δ7.06 (dd, J=7.9, 7.9 Hz, 1H), 6.60 (d, J=10.6 Hz, 1H), 6.48 (dd,J=7.8, 3.0 Hz, 1H), 6.38 (s, 1H), 6.32 (d, J=8.2 Hz, 1H), 4.80 (s, 2H),4.52 (t, J=8.6 Hz, 2H), 4.33-4.22 (m, 1H), 3.94-3.62 (m, 4H), 3.59 (s,2H), 2.99 (t, J=8.8 Hz, 2H), 2.08-1.80 (m, 3H), 1.78-1.64 (m, 1H); MS(ES+) m/z 378.8 (M+1).

EXAMPLE 11.40 AND EXAMPLE 11.41 Synthesis of1′-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneand1′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

1-[(4-Benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.19 g, 0.41 mmol) was suspended in methanol (20 mL) and ethyl acetate(20 mL) in a steel bomb, then 20% palladium hydroxide on carbon (0.03 g,0.04 mmol) was added. Hydrogenation was done at 120 psi in the steelbomb for 16 h. The reaction mixture was filtered through a pad ofcelite, and the filtrate was concentrated to dryness. The residue waspurified by column chromatography (ethyl acetate/methanol/ammonia,10:1:0.1) to afford1′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.015 g, 10%) as a colorless foam as the first fraction: ¹H NMR (300MHz, CDCl₃) δ7.34-7.25 (m, 1H), 7.17-6.99 (m, 3H), 6.48 (s, 0.5H), 6.44(s, 0.5H), 6.39 (s, 1H), 4.94-4.88 (m, 1H), 4.69-4.63 (m, 1H), 4.52 (t,J=8.7 Hz, 2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.76 (d, J=8.4Hz, 1H), 2.60 (d, J=8.4 Hz, 1H), 2.26 (s, 3H), 2.18-1.88 (m, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 178.1, 178.0, 161.8, 161.7, 161.2, 161.18, 142.7,142.67, 132.7, 132.6, 128.7, 128.6), 123.7, 123.6, 123.3, 123.2, 120.4,120.3, 119.8, 119.7, 118.9, 118.8, 109.6, 109.4, 93.2, 93.16, 80.5,80.4, 73.7, 73.6, 72.3, 66.8, 66.6, 58.3 58.0, 57.6, 54.7, 54.6, 46.4,46.3, 43.2, 43.17, 29.0; MS (ES+) m/z 393.0 (M+1), and1-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.04 g, 26%) as a colorless foam as the second fraction: MS (ES+) m/z379.0 (M+1).

EXAMPLE 11.42 Synthesis of1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a solution of acetone (0.04 mL, 0.53 mmol) in dichloroethane (5 mL)was added1′-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.04 g, 0.11 mmol) and sodium triacetoxyhydroborate (0.11 g, 0.53mmol), then the mixture was stirred at ambient temperature for 16 h. Thereaction mixture was concentrated to dryness, and the residue waspurified by flash chromatography with ethyl acetate/methanol/ammoniumhydroxide (15/1/0.1) to afford1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.02 g, 54%) as a colorless foam; ¹H NMR (300 MHz, CDCl₃) δ7.38-7.25(m, 1H), 7.18-7.04 (m, 3H), 6.50 (s, 0.5H), 6.44 (s, 0.5H), 6.41 (s,1H), 4.92 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz,2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.85-2.55 (m, 3H),2.37-2.03 (m, 2H), 1.05-0.98 (m, 6H); MS (ES+) m/z 421.0 (M+1).

EXAMPLE 11.43 Synthesis of1′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.06 g, 0.20 mmol) in anhydrous N,N-dimethylformamide (10 mL) was addedsodium hydride (60% in mineral oil, 0.20 g, 0.50 mmol) at ambienttemperature. The mixture was stirred for 15 min, and iodomethane (0.14g, 1.0 mmol) was added in one portion. The reaction mixture was stirredat ambient temperature for 1 h, and then concentrated to dryness. Theresidue was purified by flash chromatography with ethyl acetate inhexanes (0% to 30% gradient) to afford1′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.06 g, 88%): mp 187-190° C.; ¹H NMR (300 MHz, CDCl₃) δ7.32 (dd, J=7.4,7.4 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.91 (d,J=7.4 Hz, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 4.79 (ABq, 2H), 4.52 (t,J=8.5 Hz, 2H), 3.28 (s, 3H), 2.98 (t, J=8.5 Hz, 2H); ¹³C NMR (75 MHz,CDCl₃) δ 177.7, 161.6, 161.1, 142.9, 132.7, 128.6, 123.6, 123.2, 120.0,119.7, 118.8, 108.1, 93.0, 80.4, 72.2, 57.6, 28.9, 26.6; MS (ES+) m/z294.1 (M+1).

EXAMPLE 11.44 Synthesis of1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A round bottom flask was charged with4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(0.50 g, 1.27 mmol), sodium azide (0.21 g, 3.17 mmol), and triethylaminehydrochloride (0.45 g, 3.17 mmol) in toluene (20 mL). The reactionmixture was refluxed under argon for 24 h. After cooling to ambienttemperature, the product was extracted with water. 36% hydrochloric acidwas added dropwise to the aqueous layer. The solid was filtrated anddried under reduced pressure to afford1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.38 g, 58%); ¹H NMR (300 MHz, CDCl₃) δ8.02 (d, J=8.0 Hz, 2H), 7.55 (d,J=8.0 Hz, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.05-6.94(m, 2H), 6.47 (s, 1H), 6.40 (s, 1H), 5.01 (ABq, 2H), 4.79 (ABq, 2H),4.53-4.38 (m, 2H), 3.03-2.82 (m, 2H); ¹³C NMR (75 MHz, CD₃OD) δ177.6,161.6, 161.2, 142.5, 140.1, 132.6, 129.1, 128.6, 127.9, 124.2, 123.6,120.8, 120.4, 119.4, 109.8, 92.9, 80.3, 72.5, 57.4, 43.3, 28.8; MS (ES+)m/z 437.9 (M+1).

EXAMPLE 11.45 Synthesis of1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.30 g, 2.7 mmol) and 10% wt. palladium on carbon (0.25 g) in drymethanol (14 mL) was hydrogenated at ambient temperature under a balloonpressure for 16 h. The mixture was filtered through a pad of celite andconcentrated in vacuo to dryness. The residue was subjected to columnchromatography (hexanes/ethyl acetate from 2:1 to 1:1) to afford1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.97 g, 93%) as a colorless solid: mp 225-227° C.; ¹H NMR (300 MHz,CDCl₃) δ9.48 (s, 1H), 7.30-7.22 (m, 1H), 7.20-7.11 (m, 2H), 7.06-6.94(m, 2H), 6.81-6.76 (m, 1H), 6.72-6.69 (m, 1H), 6.68-6.63 (m, 1H), 6.46(s, 1H), 6.43 (s, 1H), 4.85 (ABq, 2H), 4.79 (ABq, 2H), 4.55-4.46 (m,2H), 3.02-2.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.0, 161.1, 160.6,157.6, 142.2, 137.6, 132.0, 129.7, 128.6, 123.6, 123.0, 120.4, 119.9,118.9, 117.7, 114.4, 113.6, 109.4, 92.5, 79.8, 72.1, 56.9, 42.9, 28.3;MS (ES+) m/z 386.0 (M+1).

EXAMPLE 11.46 Synthesis oft-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A suspension of1′-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.45 g, 1.0 mmol), morpholine (0.26 g, 3.0 mmol),dicyclohexyloxalylhydrazide (0.14 g, 0.5 mmol), tetrabutylammoniumbromide (0.34 g, 1 mmol), copper (II) oxide (0.05 g, 0.6 mmol) andcesium carbonate (0.65 g, 2.0 mmol) was heated in microwave reactor at130° C. for 10 min. The reaction mixture was concentrated under reducedpressure, and the residue was subjected to column chromatography withdichloromethanemethanol (100:1-10:1) to afford1′-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneas a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.35-6.74 (m, 8H), (0.09g, 19%), 6.45 (s, 1H), 6.41 (s, 1H), 4.87 (ABq, 2H), 4.81 (ABq, 2H),4.52 (t, J=8.7, 8.7 Hz, 2H), 4.01-3.74 (m, 4H), 3.25-3.07 (m, 4H),3.05-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 161.8, 161.3, 142.1,132.8, 128.6 (2C), 123.8, 123.3, 120.2, 119.9, 118.9, 116.0, 109.3,93.2, 80.6, 72.3, 66.6, 57.7, 49.4, 43.6, 29.0; MS (ES+) m/z 454.87(M+1).

EXAMPLE 11.47 Synthesis of6-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of6-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.65 g, 4.1 mmol), benzophenone imine (0.90 g, 4.92 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.46 g, 0.51 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.96 g, 1.6 mmol) intoluene (50.0 mL) was added sodium tert-butoxide (0.55 g, 5.8 mmol). Thesolution was heated at reflux for 2 h, cooled to ambient temperature,diluted with ethyl acetate (75 mL), filtered through celite andconcentrated in vacuo to dryness. The residue was dissolved intetrahydrofuran (150 mL) and 3 M hydrochloric acid (15 mL). The solutionwas diluted in ethyl acetate (250 mL), and adjusted to basic with 5 MNaOH. The aqueous phase was further extracted with ethyl acetate (2×100mL). The combined organic solution was dried over magnesium sulfate,filtered and concentrated in vacuo to dryness. The residue was purifiedby flash chromatography with ethyl acetate in hexanes (15% to 50%gradient) to afford6-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.84 g, 61%) as a colorless solid: mp 71-74° C.; ¹H NMR (300 MHz,CDCl₃, mixture of diastereomers) δ7.29-7.22 (m, 1H), 7.14-6.95 (m, 3H),6.46 (d, J=8.1 Hz, 1H), 6.26 (d, J=2.0 Hz, 1H), 6.10 (dd, J=8.1, 2.0 Hz,1H), 4.75 (ABq, 2H), 4.31-4.19 (m, 1H), 3.99-3.61 (m, 6H), 2.08-1.80 (m,3H), 1.77-1.61 (m, 1H); ¹³C NMR (75 MHz, CDCl₃, mixture ofdiastereomers) δ178.3 (2), 162.1, 148.4, 142.9 (2), 132.7 (2), 128.6(2), 123.7, 123.6 (2), 123.2 (2), 118.8 (2), 109.4 (2), 108.4, 97.2,80.3 (2), 68.2 (2), 57.6 (2), 44.5 (2), 29.1 (2), 25.6 (2); MS (ES+) m/z337.0 (M+1).

EXAMPLE 11.48 Synthesis ofN-{2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}methanesulfonamide

To a stirred solution of6-amino-1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.20 g, 0.6 mmol), triethylamine (0.09 g, 0.9 mmol) in dichloromethanewas added methanesulfonyl chloride (0.07 g, 0.6 mmol). The solution wasstirred at 0° C. for 4 h, then concentrated in vacuo to dryness. Theresidue was purified by flash chromatography with ethyl acetate inhexanes (50% to 75% gradient) to affordN-{2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}methanesulfonamide(0.15 g, 61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)(diastereomers) δ7.75 (d, J=5.5 Hz, 1H), 7.28 (dd, J=7.4, 7.4 Hz, 1H),7.13-6.97 (m, 3H), 6.75 (dd, J=8.3, 1.4 Hz, 1H), 6.59-6.42 (m, 2H), 4.93(d, J=9.2 Hz, 1H), 4.66 (d, J=9.2 Hz, 1H), 4.38-4.20 (m, 1H), 3.99-3.64(m, 4H), 2.92 (s, 3H), 2.16-1.77 (m, 3H), 1.77-1.61 (m, 1H); ¹³C NMR (75MHz, CDCl₃) (diastereomers) δ178.2 (2), 161.7 (2), 142.8 (2), 138.9,131.9 (2), 129.0 (2), 125.0 (2), 124.0 (2), 123.7 (2), 113.1 (2), 109.8(2), 102.5 (2), 80.3 (2), 68.2 (2), 57.7 (2), 44.7 (2), 39.2, 25.6 (2);MS (ES+) m/z 415.0 (M+1).

EXAMPLE 11.49 Synthesis of6-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

A suspension of6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(7.80 g, 18.86 mmol) and 10% palladium on carbon (2.00 g, 1.88 mmol) inmethanol (150 mL) was hydrogenated for 54 h. The mixture was filteredthrough a pad of celite, the filtrate was concentrated in vacuo, and theresidue was crystallized from diethyl ether to give6-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(11H)-one(5.20 g, 85%) as a colorless solid: mp 101-103° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃) δ7.32-7.27 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.02(m, 1H), 6.92-6.89 (m, 1H), 6.40-6.38 (m, 1H), 6.20-6.12 (m, 2H), 4.77(AB, 2H), 3.86-3.70 (m, 2H), 1.64-1.59 (m, 3H), 0.99 (d, J=6.0 Hz, 6H);MS (ES+) m/z 324.3 (M+1).

EXAMPLE 11.50 Synthesis of6-hydroxy-1′-(3-methylbutyl)-5-(trifluoroacetyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of6-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.00 g, 3.10 mmol) in tetrahydrofuran (30 mL) was addedisopropylmagnesium chloride (1.6 mL, 2.0M tetrahydronfuran solution,3.20 mmol) at 0° C. The mixture was allowed to stir at 0° C. for 1 h,then trifluoroacetic anhydride (0.8 mL, 5.75 mmol) was added. Themixture was stirred at ambient temperature for 52 h, quenched withsaturated sodium bicarbonate solution and stirred for 30 min. Theresulting solution was extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo. The residue wassubjected to column chromatography with ethyl acetate in hexanes(gradient: 10% to 30%) to give6-hydroxy-1-(3-methylbutyl)-5-(trifluoroacetyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.12 g, 9%): mp 87-88° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃)

11.78 (s, 1H), 7.38-7.32 (m, 1H), 7.14-7.03 (m, 3H), 7.07-7.02 (m, 1H),6.94-6.89 (d, J=9.0 Hz, 1H), 6.58 (s, 1H), 4.90 (ABq, 2H), 3.95-3.86 (m,1H), 3.71-3.62 (m, 1H), 1.66-1.59 (m, 3H), 0.98 (d, J=6.0 Hz, 6H); MS(ES+) m/z 420.1 (M+1).

EXAMPLE 11.51 Synthesis of tert-butyl(3R)-3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)amino]pyrrolidine-1-carboxylate

To a stirred solution of6-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.80 g, 1.73 mmol), (R)-1-Boc-3-aminopyrrolidine (0.48 g, 2.59 mmol)and (2-biphenyl)di-tert-butylphosphine (0.08 g, 0.28 mmol) in toluene(15 mL) was added palladium(II) acetate (0.09 g, 0.14 mmol) followed bythe addition of sodium tert-butoxide (0.42 g, 4.3 mmol). The mixture wasstirred at 100° C. for 18 h. The mixture was filtered through a pad ofcelite, and the filtrate was concentrated in vacuo. The residue wassubjected to column chromatography (ethyl acetate/hexane; 1/2) to affordtert-butyl(3R)-3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)amino]pyrrolidine-1-carboxylate(0.47 g, 48%): ¹H NMR (300 MHz, CDCl₃) δ7.32-7.24 (m, 1H), 7.17 (d,J=7.4 Hz, 1H), 7.05 (dd, J=7.4 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H),6.76-6.69 (m, 1H), 6.45 (d, J=8.2 Hz, 1H), 6.36 (d, J=3.2 Hz, 1H), 6.19(d, J=2.0 Hz, 1H), 6.02 (dd, J=8.2, 2.0 Hz, 1H), 5.05 (d, J=16.2 Hz,1H), 4.95-4.81 (m, 2H), 4.65 (d, J=9.0 Hz, 1H), 4.00-3.90 (m, 1H),3.88-3.76 (m, 1H), 3.73-3.57 (m, 1H), 3.52-3.34 (m, 2H), 3.30-3.11 (m,1H), 2.23-2.06 (m, 1H), 1.96-1.77 (m, 1H), 1.45 (s, 9H); MS (ES+) m/z570.2 (M+1).

EXAMPLE 11.52 Synthesis of6-[(3R)-pyrrolidin-3-ylamino]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of tert-butyl(3R)-3-[(2′-oxo-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)amino]pyrrolidine-1-carboxylate(0.22 g, 0.47 mmol) in methanol (10 mL) was added 4 M hydrogen chloridein dioxane (2 mL, 8.0 mmol). The mixture was stirred at ambienttemperature for 16 h. Solvent and excess hydrogen chloride were removedunder vacuum. The residue was treated with methanol and diethyl ether toform a solid.6-[(3R)-Pyrrolidin-3-ylamino]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained through filtration (0.12 g, 47%) as a colorless solid: mp122-125° C.; ¹H NMR (300 MHz, CD₃OD) δ7.40 (dd, J=7.9, 7.9 Hz, 1H),7.26-7.13 (m, 3H), 7.05-6.99 (m, 1H), 6.68 (d, J=3.2 Hz, 1H), 6.58-6.47(m, 2H), 6.34 (d, J=8.2 Hz, 1H), 5.24 (d, J=16.7 Hz, 1H), 5.05 (d,J=16.7 Hz, 1H), 4.94 (d, J=9.1 Hz, 1H), 4.78 (d, J=9.1 Hz, 1H),4.31-4.24 (m, 1H), 3.67-3.42 (m, 4H), 2.53-2.35 (m, 1H), 2.27-2.11 (m,1H); ¹³C NMR (75 MHz, CD₃OD) δ178.1, 162.3 (m), 152.8, 141.5, 132.2,128.7, 123.7, 123.6, 123.4, 120.8, 117.3, 112.8 (m), 109.5, 109.1, 79.8,57.7, 54.2 (m), 49.4, 44.3, 36.3, 29.5; MS (ES+) m/z 470.2 (M+1).

EXAMPLE 11.53 Synthesis of6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a solution of1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.69 g, 3.43 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogenwas added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran,10 mL, 10 mmol), and the mixture was stirred at ambient temperature for16 h. The reaction mixture was concentrated, and the residue wasre-dissolved in ethyl acetate (25 mL), washed with water (2×20 mL) andbrine (20 mL), dried over sodium sulfate, filtered, and concentrated.The residue was purified by column chromatography with 40% ethyl acetatein hexanes to afford6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(1.00 g, 86%) as a colorless solid: mp 72-74° C.; ¹H NMR (300 MHz,CDCl₃) δ7.29 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.18-7.01 (m, 3H), 6.80-6.67(br., 1H), 6.44 (d, J=8.4 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 6.17-6.09 (m,1H), 4.96-4.90 (m, 1H), 4.69-4.63 (m, 1H), 4.36-4.24 (m, 1H), 4.00-3.71(m, 4H), 2.12-1.61 (m, 4H); MS (ES+) m/z 338.1 (M+1).

EXAMPLE 11.54 Synthesis of6-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of triphenylphosphine (0.23 g, 0.89 mmol) inanhydrous tetrahydronfuran (200 mL) at 0° C. under nitrogen were addeddiethyl azodicarboxylate (0.14 mL, 0.89 mmol), isopropanol (0.23 mL,2.97 mmol) and6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.20 g, 0.59 mmol). The reaction mixture was stirred at ambienttemperature for 16 h, and then the reaction was quenched with ammoniumchloride solution. The solvent was removed, and the residue wasdissolved in ethyl acetate (100 mL), which was washed with water, brine,dried over sodium sulfate and filtered. The filtrate was concentrated todryness, and the residue was purified by flash chromatograph with 25%ethyl acetate in hexanes to afford6-(1-methylethoxy)-1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.19 g, 85%) as colorless liquid; ¹H NMR (300 MHz, CDCl₃) δ7.33-7.25(m, 1H), 7.16-6.99 (m, 3H), 6.58 (d, J=8.4 Hz, 1H), 6.50 (d, J=1.8 Hz,1H), 6.33 (dd, J=8.4, 2.1 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d,J=9.0 Hz, 1H), 4.53-4.43 (m, 1H), 4.33-4.23 (m, 1H), 4.00-3.66 (m, 4H),2.10-1.66 (m, 4H), 1.31 (d, J=6.0 Hz, 6H); MS (ES+) m/z 380.0 (M+1),402.0 (M+23).

EXAMPLE 11.55 Synthesis of tert-butyl(3S)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy}pyrrolidine-1-carboxylate

Following the procedure as described in EXAMPLE 11.54 and makingnon-critical variations using (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate to replace isopropanol, tert-butyl(3S)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylatewas obtained (75%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.33-7.26 (m, 1H), 7.17-7.00 (m, 3H), 6.64-6.57 (m, 1H), 6.50-6.45 (m,1H), 6.35-6.28 (m, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.85-4.78 (m, 1H), 4.69(d, J=9.0 Hz, 1H), 4.33-4.22 (m, 1H), 4.00-3.40 (m, 8H), 2.22-1.65 (m,6H), 1.47 (s, 9H); MS (ES+) m/z 529.1 (M+23).

EXAMPLE 11.56 Synthesis of6-[(3S)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a stirred solution of tert-butyl(3S)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylate(0.33 g, 0.65 mmol) in dichloromethane (5 mL) was added 4 M hydrogenchloride in dioxane (4 mL, 16 mmol). The mixture was stirred at ambienttemperature for 3 h, then anhydrous diethyl ether (20 mL) was added. Thewhite solid was precipitated out, filtered, washed with diethyl etherand dried to afford6-[(3S)-pyrrolidin-3-yloxy]-1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.24 g, 82%) as a colorless solid: mp 119-121° C.; ¹H NMR(300 MHz, CD₃OD) δ7.38-7.03 (m, 4H), 6.68-6.59 (m, 2H), 6.48-6.41 (m,1H), 5.20-5.14 (m, 1H), 4.92-4.85 (m, 1H), 4.73 (d, J=9.3 Hz, 1H),4.37-4.24 (m, 1H), 4.00-3.38 (m, 8H), 2.36-1.66 (m, 6H); MS (ES+) m/z407.1 (M+1).

EXAMPLE 11.57 Synthesis of tent-butyl(3R)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylate

Following the procedure as described in EXAMPLE 11.54 and makingnon-critical variations using (S)-tert-butyl3-hydroxypyrrolidine-1-carboxylate to replace isopropanol, tert-butyl(3R)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylatewas obtained (80%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.34-7.26 (m, 1H), 7.16-7.00 (m, 3H), 6.60 (d, J=8.1 Hz, 1H), 6.47 (d,J=2.1 Hz, 1H), 6.32 (d, J=8.4, 2.1 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H),4.85-4.78 (m, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.33-4.22 (m, 1H), 4.00-3.39(m, 8H), 2.23-1.65 (m, 6H), 1.47 (s, 9H); MS (ES+) m/z 529.1 (M+23).

EXAMPLE 11.58 Synthesis of6-[(3R)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 11.56 and makingnon-critical variations using tert-butyl(3R)-3-({2′-oxo-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylateto replace tert-butyl(3S)-3-({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)pyrrolidine-1-carboxylate,6-[(3R)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride was obtained (87%) as a colorless solid: mp 120-130° C.;¹H NMR (300 MHz, CD₃OD) δ7.38-7.04 (m, 4H), 6.68-6.59 (m, 2H), 6.48-6.41(m, 1H), 5.20-5.14 (m, 1H), 4.92-4.85 (m, 1H), 4.73-4.70 (m, 1H),4.36-4.24 (m, 1H), 3.99-3.38 (m, 8H), 2.36-1.66 (m, 6H); MS (ES+) m/z407.1 (M+1).

EXAMPLE 11.59 Synthesis of tert-butyl3-[(2′-oxo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl3-[(2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate(0.19 g, 0.45 mol) in N,N-dimethyl formamide (10 mL) was added sodiumhydride (0.02 g, 0.54 mmol) slowly at 0° C. After 30 min,2-(bromomethyl)-5-(trifluoromethyl)furan (0.12 g, 0.54 mmol) was added.The mixture was stirred at ambient temperature for 16 h, and thenquenched with saturated ammonium chloride (10 mL). The mixture wasextracted with ethyl acetate (3×20 mL). The combined organic solutionwas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography (ethyl acetate/hexanes, 1/2) to afford tert-butyl3-[(2′-oxo-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl)oxy]pyrrolidine-1-carboxylate(0.14 g, 55%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.29 (t,J=7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.97 (d,J=7.8 Hz, 1H), 6.76-6.70 (m, 1H), 6.54 (d, J=8.2 Hz, 1H), 6.47 (s, 1H),6.40-6.35 (m, 1H), 6.30 (d, J=8.2 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.95(d, J=9.0 Hz, 1H), 4.86 (d, J=16.2 Hz, 1H), 4.80 (br s, 1H), 4.69 (d,J=9.0 Hz, 1H), 3.64-3.37 (m, 4H), 2.22-1.96 (m, 2H), 1.45 (s, 9H); MS(ES+) m/z 593.2 (M+23).

EXAMPLE 11.60 Synthesis of1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione

To a solution of({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)aceticacid (0.42 g, 1.06 mmol) in benzene were added oxaly chloride (0.28 mL,3.18 mmol) and a drop of N,N-dimethyl formamide, then the reactionmixture was refluxed for 16 h. The mixture was evaporated to dryness anddried over high vacuum pump. The residue was re-dissolved in anhydrousdichloromethane (30 mL), and then aluminum trichloride (0.21 g, 1.59mmol) was added. The reaction mixture was stirred at ambient temperaturefor 16 h, and then refluxed for 2 h. The reaction was quenched bysaturated ammonium chloride, and then extracted with dichloromethane(2×50 mL). The combined organic phase was dried over sodium sulfate,filtered, concentrated and purified by flash chromatography with 50%ethyl acetate in hexanes to give1-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione(0.28 g, 69%) as a colorless solid: mp 142-144° C.; ¹H NMR (300 MHz,CDCl₃) δ7.36-7.29 (m, 1H), 7.16-7.00 (m, 4H), 6.64-6.60 (m, 1H), 5.08(d, J=9.3 Hz, 1H), 4.85-4.80 (m, 1H), 4.61 (s, 2H), 4.31-4.19 (m, 1H),3.98-3.68 (m, 4H), 2.11-1.84 (m, 3H), 1.76-1.62 (m, 1H); MS (ES+) m/z377.9 (M+1), 399.9 (M+23).

EXAMPLE 11.61 Synthesis of1′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.5 and makingnon-critical variations using tert-butyl3-[(2′-oxo-5,6-dihydrospiro[benzo-[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylateto replace tert-butyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate,tetrahydrofuran to replace dichloromethane,1-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (66%) as a colorless solid: mp 85-95° C. (dichloromethane);¹H NMR (300 MHz, CDCl₃) (diastereomers) δ7.309 (dd, J=7.8, 1.2 Hz, 0.5Hz), 7.305 (dd, J=7.8, 1.2 Hz, 0.5H), 7.180 (d, J=7.5, Hz, 0.5H), 7.177(d, J=7.5 Hz, 0.5H), 7.063 (dd, J=7.5, 0.6 Hz, 0.5H), 7.060 (dd, J=7.5,0.6 Hz, 0.5H), 6.96 (d, J=7.8 Hz, 1H), 6.452 (s, 0.5H), 6.450 (s, 0.5H),6.41 (s, 1H), 4.92 (d, J=9.0 Hz, 0.5H), 4.91 (d, J=9.0 Hz, 0.5H), 4.67(d, J=9.0 Hz, 0.5H), 4.66 (d, J=9.0 Hz, 0.5H), 4.54 (t, J=8.7 Hz, 2H),3.85 (dd, J=14.1, 8.7 Hz, 0.5H), 3.83 (dd, J=13.8, 7.8 Hz, 0.5H), 3.67(dd, J=13.8, 7.5 Hz, 0.5H), 3.65 (dd, J=13.9, 6.8 Hz, 0.5H), 3.18-2.92(m, 4H), 2.84-2.65 (m, 2H), 2.55-2.36 (m, 2H), 2.02-1.89 (m, 1H),1.67-1.53 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ 178.2,161.9, 161.4, 142.41, 142.38, 132.9, 128.9, 124.1, 123.5, 120.3, 120.2,120.1, 120.0, 118.8, 108.7, 93.3, 80.7, 72.48, 72.47, 57.8, 50.4, 46.30,46.25, 43.41, 43.39, 37.8, 29.91, 29.86, 29.13; MS (ES+) m/z 363.3(M+1).

EXAMPLE 11.62 Synthesis ofN-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxamide

To a solution of1′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.24 g, 0.65 mmol) and triethylamine (0.15 mL, 1.1 mmol) indichloromethane (5 mL) was added isopropyl isocyanate (0.10 mL, 1.0mmol) and the solution was stirred at ambient temperature for 35 min.The reaction was diluted with saturated sodium bicarbonate (40 mL) andwas extracted with dichloromethane (3×20 mL). The combined organicsolution was dried over sodium sulfate, filtered and concentrated underreduced pressure. Purification by flash column chromatography withdichloromethane/diethyl ether (2/1) affordedN-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxamide(0.24 g, 81%) as a colorless solid: mp 107-115° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) (diastereomers) δ7.31 (dd, J=7.6, 7.6 Hz, 0.5H), 7.30(dd, J=7.7, 7.7 Hz, 0.5H), 7.18 (d, J=6.8 Hz, 1H), 7.07 (dd, J=7.5, 7.5Hz, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (s, 1H), 6.42 (s, 1H), 4.912 (d,J=9.0 Hz, 0.5H), 4.906 (d, J=8.9 Hz, 0.5H), 4.67 (d, J=8.9 Hz, 0.5H),4.66 (d, J=9.0 Hz, 0.5H), 4.53 (t, J=8.6 Hz, 2H), 4.03-3.44 (m, 6H),3.35-3.17 (m, 2H), 3.00 (t, J=8.5 Hz, 2H), 2.77 (septet, J=6.9 Hz, 1H),2.09-1.98 (m, 1H), 1.87-1.73 (m, 1H), 1.15 (d, J=5.7 Hz, 3H), 1.14 (d,J=6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) (diastereomers) δ178.33, 178.26,162.0, 161.4, 156.3, 142.41, 142.36, 132.80, 132.75, 129.0, 124.25,124.23, 123.6, 120.16, 120.10, 120.07, 118.9, 118.8, 108.4, 93.39,93.36, 80.8, 72.5, 57.8, 49.2, 44.7, 44.6, 42.6, 42.5, 42.43, 42.40,37.7, 37.5, 29.35, 29.32, 29.1, 23.7; MS (ES+) m/z 448.2 (M+1).

EXAMPLE 11.63 Synthesis of1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrogen chloride

A stirred solution ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.0 g, 3.6mmol), N-methylpiperazine (3.6 g, 36.0 mmol) and formaldehyde (37% wtsolution in water, 2.9 mL, 36.0 mmol) in methanol was refluxed for 20 h.The solution was concentrated in vacuo to dryness and recrystallizedfrom ether in hexanes to afford the free base form of1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneas a pale orange solid (1.15 g, 81%). To a solution of1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.50 g, 12.7 mmol) in methanol (5 mL) was added hydrochloric acidsaturated methanol (10 mL). The precipitate that formed was filtered anddried in vacuo to afford1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onehydrogen chloride (0.65 g, quantitative) as a colorless solid: mp>175°C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ11.59 (br s, 1H), 9.43 (br s, 1H),7.41 (d, J=7.9 Hz, 1H), 7.31 (dd, J=7.6, 7.6 Hz, 1H), 7.15 (d, J=6.6 Hz,1H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.66 (s, 1H), 6.47 (s, 1H), 5.89 (s,2H), 4.86-4.73 (m, 3H), 4.61 (d, J=9.5 Hz, 1H), 3.54-3.28 (m, 4H),3.27-2.94 (m, 4H), 2.71 (s, 3H); MS (ES+) m/z 394.0 (M+1). Anal. Calcd.for C₂₀H₂₃N₃O₄.2HCl.0.5H₂O: C, 55.59; H, 5.51; N, 8.84. Found: C, 55.47;H, 5.43; N, 8.78.

EXAMPLE 11.64 Synthesis of(3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrogen chloride

A stirred solution of(3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.50g, 1.8 mmol), N-methylpiperazine (1.80 g, 17.8 mmol) and formaldehyde(37% wt solution in water, 1.45 mL, 17.8 mmol) in methanol was refluxedfor 3 h. The solution was concentrated in vacuo to dryness and dissolvedin methanol (5 mL) and hydrochloric acid saturated methanol (10 mL). Thesolution was again concentrated in vacuo to dryness, dissolved indistilled water (25 mL) and the product was precipitated upon additionof 5 M NaOH (15 mL). The solid was filtered and air dried to afford(3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.65 g, 93%). To a stirred solution of the above product (0.20 g) inmethanol (1 mL) was added hydrochloric acid saturated methanol (2 mL).The solution was stirred for 20 min, then diethyl ether (25 mL) wasadded and the suspension was filtered and air dried to afford(3S)-6-methoxy-5-methyl-1-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrogen chloride (0.19 g, 71%) as a colorless solid: mp>200° C. (dec.);¹H NMR (300 MHz, CDCl₃) δ7.71 (s, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.33 (dd,J=7.5, 7.5 Hz, 1H), 7.17-7.03 (m, 2H), 6.69 (s, 1H), 6.62 (s, 1H),4.89-4.70 (m, 2H), 4.65 (d, J=9.40 Hz, 1H), 3.77 (s, 3H), 3.52-2.91 (m,5H), 2.72 (s, 3H), 1.98 (s, 3H); MS (ES+) m/z 394.0 (M+1); Anal. Calcd.for C₂₃H₂₇N₃O₃.2.5HCl-2.5H₂O: C, 52.15; H, 6.57; N, 7.93. Found: C,52.07; H, 6.32; N, 8.50.

EXAMPLE 11.65 Synthesis of(3R)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrogen chloride

Following the procedure as described in EXAMPLE 11.64 and makingnon-critical variations using(3R)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one toreplace(3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,(3R)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrogen chloride was obtained (27%) as a colorless solid: mp>200° C.(dec.); ¹H NMR (300 MHz, CDCl₃) δ7.57-7.49 (m, 2H), 7.39 (d, J=7.9 Hz,1H), 7.29 (t, J=7.5 Hz, 1H), 7.15-6.99 (m, 2H), 6.65 (s, 1H), 6.59 (s,1H), 4.87-4.67 (m, 2H), 4.62 (d, J=9.4 Hz, 1H), 3.73 (s, 3H), 3.51-2.86(m, 5H), 2.69 (s, 3H), 1.95 (s, 3H); MS (ES+) m/z 393.99 (M+1); Anal.Calcd. for C₂₃H₂₇N₃O₃.2HCl.2H₂O: C, 54.98; H, 6.62; N, 8.36. Found: C,54.92; H, 6.33; N, 8.32.

EXAMPLE 11.66 Synthesis of(3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

1′-[(2R)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas resolved on chiral semi-prep HPLC IA column with 99%tert-butylmethyl ether and 1% acetonitrile to afford(3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(66%): ¹H NMR (300 MHz, CDCl₃) δ7.34-6.97 (m, 4H), 6.48 (s, 1H), 6.38(s, 1H), 4.77 (ABq, 2H), 4.50 (t, J=8.6 Hz, 2H), 4.32-4.21 (m, 1H),3.92-3.68 (m, 4H), 2.96 (t, J=8.4 Hz, 2H), 2.10-1.64 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 178.2, 161.7, 161.2, 142.8, 132.7, 128.6, 123.6,123.2, 120.4, 119.8, 118.9, 109.5, 93.1, 80.7, 76.8, 72.3, 68.1, 57.6,44.5, 29.0, 29.0, 25.6; MS (ES+) m/z 363.8 (M+1).

EXAMPLE 11.67 Synthesis of(3R)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

1′-[(2R)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas resolved on chiral semi-prep HPLC IA column with tert-butylmethylether (99%) and acetonitrile (1%) to afford(3R)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(66%): ¹H NMR (300 MHz, CDCl₃) δ 7.35-6.98 (m, 4H), 6.47 (s, 1H), 6.38(s, 1H), 4.78 (Abq, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.31-4.21 (m, 1H),3.99-3.63 (m, 4H), 3.03-2.90 (m, 2H), 2.10-1.62 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ178.1, 161.7, 161.2, 142.8, 132.6, 128.6, 123.6, 123.2,120.3, 119.8, 118.8, 109.4, 93.1, 80.6, 76.9, 72.3, 68.2, 57.6, 44.6,29.2, 29.0, 25.5; MS (ES+) m/z 363.8 (M+1).

EXAMPLE 11.68 Synthesis of(3R)-1-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

1′-[(2S)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas resolved on chiral semi-prep HPLC IA column with tert-butylmethylether (100%) to afford(3R)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(64%): ¹H NMR (300 MHz, CDCl₃) δ7.32-6.98 (m, 4H), 6.47 (s, 1H), 6.38(s, 1H), 4.77 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.31-4.21 (m, 1H),3.98-3.64 (m, 4H), 3.05-2.88 (m, 2H), 2.09-1.64 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 178.2, 161.7, 161.2, 142.8, 132.6, 128.6, 123.6, 123.2,120.3, 119.8, 118.8, 109.4, 93.1, 80.6, 76.9, 72.3, 68.2, 57.6, 44.6,29.2, 29.0, 25.5; MS (ES+) m/z 363.8 (M+1).

EXAMPLE 11.69 Synthesis of(3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

1′-[(2S)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas resolved on chiral semi-prep HPLC IA column with tert-butylmethylether (100%) to afford(3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(64%): ¹H NMR (300 MHz, CDCl₃) δ 7.32-6.97 (m, 4H), 6.48 (s, 1H), 6.38(s, 1H), 4.77 (ABq, 2H), 4.51 (t, J=8.3 Hz, 2H), 4.32-4.21 (m, 1H),3.91-3.68 (m, 4H), 2.97 (t, J=8.5 Hz, 2H), 2.10-1.63 (m, 4H); ¹³C NMR(75 MHz, CDCl₃) δ 178.3, 161.7, 161.2, 142.8, 132.7, 128.6, 123.6,123.2, 120.4, 119.8, 118.9, 109.5, 93.1, 80.6, 76.8, 72.3, 68.1, 57.6,44.5, 29.0, 25.6; MS (ES+) m/z 363.8 (M+1).

EXAMPLE 11.70 Synthesis of1′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of1-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.235 g, 0.623 mmol) in dry N,N-dimethylformamide (10 mL) was addedsodium hydride (60% in mineral oil, 0.04 g, 1.04 mmol) at ambienttemperature. The mixture was stirred for 15 min, and iodomethane (0.28g, 2.0 mmol) was added in one portion. The reaction mixture was stirredat ambient temperature for 1 h, and concentrated to dryness. The residuewas purified by flash chromatography (hexanes/ethyl acetate; gradient 0%to 30%) to afford1′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.15 g, 62%) as colorless solid: mp 72-76° C.; ¹H NMR (300 MHz, CDCl₃)δ7.33 (dd, J=7.5, 7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.09 (dd, J=7.5,7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.46-6.38 (m, 2H), 4.77 (ABq, 2H),4.53 (t, J=8.6 Hz, 2H), 4.03-3.75 (m, 3H), 3.11-2.83 (m, 5H), 2.61-2.42(m, 1H), 2.42-2.27 (m, 1H), 2.26-2.07 (m, 1H), 2.03-1.84 (m, 1H); ¹³CNMR (75 MHz, CDCl₃) δ178.4, 178.4, 175.1, 175.0, 161.8, 161.3, 161.2,142.1, 141.9, 132.5, 132.4, 128.9 (2C), 124.3, 124.2, 123.7 (2C), 120.0,119.9, 119.7, 119.6, 118.6, 118.5, 108.0, 93.2, 80.5, 72.3, 58.1, 58.0,57.5 (2C), 43.0, 42.9, 29.3, 29.2, 28.9, 28.7 (2C), 22.6 (20); MS (ES+)m/z 391.1 (M+1).

EXAMPLE 11.71 Synthesis of1-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A mixture of1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.32 g, 0.84 mmol), tetrabutylammonium bromide (0.05 g, 0.16 mmol),aqueous sodium hydroxide (0.10 g, 2.52 mmol) and dimethyl sulfate (0.21g, 1.68 mmol) in anhydrous tetrahydrofuran (5 mL), was stirred at anambient temperature for 1 h. The mixture was concentrated in vacuo todryness. The residue was purified by column chromatography with ethylacetate (30%) in hexanes to afford1′-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.13 g, 40%): mp 98-102° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.39 (dd, J=7.7,7.7 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.07 (dd, J=7.5, 7.5 Hz, 1H), 6.88(d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.05 (s, 1H), 5.84 (d, J=6.2 Hz, 2H),4.74 (ABq, 2H), 3.93-3.88 (m, 2H), 3.82-3.74 (m, 1H), 2.92 (d, J=4.0 Hz,3H), 2.55-2.40 (m, 1H), 2.36-2.26 (m, 1H), 2.20-2.07 (m, 1H), 1.95-1.85(m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 178.1, 175.2, 175.1, 156.1,156.0, 149.1, 142.5, 142.4, 142.2, 142.0, 132.1, 132.0, 129.2, 124.5,124.4, 123.9, 123.8, 119.0, 118.9, 108.1, 102.8, 102.7, 101.6, 93.8,93.7, 80.5, 80.4, 58.2, 58.1, 58.0, 57.9, 43.1, 43.0, 29.3, 29.2, 28.8,28.7, 22.8, 22.7; MS (ES+) m/z 417.3 (M+1).

EXAMPLE 11.72 Synthesis of1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a mixture ofN′-hydroxy-2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethanimidamide(0.53 g, 1.50 mmol) in dichloromethane (30 mL) was addeddiisopropylethyl amine (3.88 g, 3.00 mmol) and trifluoroacetic anhydride(0.41 g, 1.95 mmol) at 0° C. to give a clear yellow solution. Thereaction solution was stirred for 2 h. The organic layer was washed withsaturated aqueous ammonium chloride (3×15 mL), brine (3×15 mL), driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography with ethyl acetate in hexanes (30%) to afford1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.47 g, 73%) as a colourless solid: mp 139-140° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.30 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H),7.14 (d, J=7.8 Hz, 1H), 7.05 (ddd, J=7.5, 7.5, 0.8 Hz, 1H), 6.67 (s,1H), 6.23 (s, 1H), 5.89 (d, J=3.8 Hz, 2H), 5.28 (ABq, 2H), 4.74 (ABq,2H); ¹³C NMR (75 MHz, DMSO-d₆) 177.1, 167.8, 165.5 (d, ²J_(CF)=42 Hz),155.7, 148.9, 142.2, 141.8, 132.1, 129.3, 124.2, 124.0, 120.2, 116.1 (d,¹J_(CF)=273 Hz), 109.9, 103.5, 101.9, 93.8, 79.9, 57.9, 35.9; MS (ES+)m/z 432.2 (M+1).

EXAMPLE 11.73 Synthesis ofN-isopropyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxamide

To a mixture of1-(2-piperidin-3-ylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.82 g, 2.09 mmol) and diispropylethylamine (1.08 g, 8.37 mmol) inanhydrous dichloromethane (25 mL) was added isopropyl isocyanate (0.36g, 4.18 mmol) at 0° C. The reaction mixture was stirred at ambienttemperature for 16 h. The reaction was quenched by addition of saturatedaqueous ammonium chloride solution (100 mL) and extracted withdichloromethane (3×50 mL). The combined organic solution was washed withbrine (80 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to dryness. The residue was purified by columnchromatography with methanol in dichloromethane (2% to 10% gradient) togiveN-isopropyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxamide(0.21 g, 21%) as a colorless solid: mp 206-208° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 7.34 (ddd, J=7.8, 7.8, 1.0Hz, 1H), 7.16 (dd, J=6.4, 6.4 Hz, 2H), 7.05 (dd, J=7.3, 7.3 Hz, 1H),6.69 (s, 1H), 6.16 (s, 1H), 5.97 (d, J=7.6 Hz, 1H), 5.92 (s, 2H), 4.77(d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 3.84-3.60 (m, 5H), 2.66 (t,J=10.7 Hz, 1H), 2.55-2.47 (m, 1H), 1.85-1.81 (m, 1H), 1.57-1.10 (m, 6H),1.03 (d, J=6.6 Hz, 3H), 0.97 (d, J=6.6 Hz, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.6, 156.5, 155.4, 148.2, 142.2, 141.7, 131.9, 128.9,123.6, 122.9, 119.7, 109.0, 102.8, 101.4, 93.3, 79.8, 57.4, 48.8, 43.9,41.7, 37.5, 33.0, 30.6, 30.5, 24.4, 22.9, 22.8; MS (ES+) m/z 478.5(M+1).

EXAMPLE 11.74 Synthesis of5-[(2′-oxospiro[furo[2,3-][1,3′]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]thiophene-3-carbonitrile

To a suspended mixture of1′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.456 g, 1.0 mmol) and zinc cyanide (0.117 g, 1.0 mmol) in anhydrousN,N-dimethylformamide (5 mL) was addedtetrakis(triphenylphosphine)palladium (0.04 g, 0.03 mmol). The reactionmixture was put into a microwave reactor set at 100 W at 133° C. for 7min. The solid was filtered and washed with ethyl acetate (40 mL). Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby column chromatography with ethyl acetate in hexanes (10% to 30%gradient) to give5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]thiophene-3-carbonitrile(0.25 g, 62%) as a colorless solid: mp 207-209° C.(dichloromethane/hexane); ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (d, J=1.3 Hz,1H), 7.63 (d, J=1.3 Hz, 1H), 7.33 (dd, J=7.8, 1.1 Hz, 1H), 7.23-7.19 (m,2H), 7.06 (d, J=7.4, 0.8 Hz, 1H), 6.71 (s, 1H), 6.15 (s, 1H), 5.93 (d,J=1.5 Hz, 2H), 5.14 (d, J=4.6 Hz, 2H), 4.81 (d, J=9.4 Hz, 1H), 4.69 (d,J=9.4 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.5, 155.4, 148.3, 141.7,141.5, 141.3, 137.8, 131.5, 128.8, 127.9, 123.7, 123.3, 119.4, 115.1,109.3, 108.7, 102.8, 101.4, 93.3, 79.7, 57.3, 37.9; MS (ES+) m/z 403.2(M+1).

EXAMPLE 11.75 Synthesis of2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile

To a suspended mixture of7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.44g, 1.2 mmol) and zinc cyanide (0.28 g, 2.4 mmol) in anhydrousN,N-dimethylformamide (12 mL) was addedtetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol). The reactionmixture was refluxed for 3 h. The solid was filtered and washed withethyl acetate (40 mL). The filtrate was concentrated in vacuo todryness. The residue was purified by column chromatography with ethylacetate in hexanes (20% to 30% gradient) to afford2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile(0.28 g, 76%) as a colorless solid: mp 205-207° C.; ¹H NMR (300 MHz,DMSO-d₆) δ11.55 (s, 1H), 7.62 (dd, J=8.0 Hz, 1.1 Hz, 1H), 7.41 (d, J=7.0Hz, 1H), 7.12-7.07 (m, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 5.93 (dd, J=3.4,0.8 Hz, 2H), 4.78 (d, J=9.5 Hz, 1H), 4.67 (d, J=9.5 Hz, 1H); ¹³C NMR (75MHz, DMSO-d₆) δ178.4, 155.4, 148.3, 145.2, 141.7, 133.8, 131.6, 128.3,122.5, 118.9, 115.9, 103.2, 101.3, 93.1, 92.6, 79.6, 57.5; MS (ES+) m/z307.3 (M+1).

EXAMPLE 11.76 Synthesis of(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)aceticacid

Following the procedure as described in EXAMPLE 11.30 and makingnon-critical variations using ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetateto replace methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate,(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)aceticacid was obtained (83%): mp 193-196° C. (water); ¹H NMR (300 MHz,DMSO-d₆) δ 7.26-7.21 (m, 1H), 7.09-7.07 (m, 1H), 6.99-6.91 (m, 2H), 6.45(s, 1H), 6.27 (s, 1H), 4.66 (ABq, 2H), 4.29-4.05 (m, 6H); MS (ES+) m/z353.7 (M+1).

EXAMPLE 11.77 Synthesis of1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylicacid

To a solution of phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate(2.00 g, 4.65 mmol) in tetrahydrofuran (50 mL) and water (10 mL) wasadded lithium hydroxide monohydrate (1.00 g, 23.8 mmol) at ambienttemperature. The reaction mixture was stirred at ambient temperature for18 h and concentrated in vacuo. The residue was neutralized to pH 4-5with 10% w/v hydrochloric acid. The resultant precipitate was filteredand washed with diethyl ether to afford1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylicacid (1.40 g, 85%): mp 297-299° C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.54-7.43 (m, 3H), 7.32-7.28 (m, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.77(ABq, 2H), 4.12-4.02 (m, 4H), 3.15 (s, 3H); MS (ES+) m/z 376.0 (M+23).

EXAMPLE 11.78 Synthesis of3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one

A mixture of (3-bromopyridin-2-yl)methanol (0.100 g, 0.530 mmol) andthionyl chloride (0.070 mL, 0.97 mmol) in dichloromethane (3 mL) andN,N-dimethylformamide (1 drop) was stirred at ambient temperature for 16h. The reaction mixture was concentrated in vacuo and tetrahydrofuran (5mL) and N,N-dimethylformamide (5 mL) were added, followed by2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.121 g, 0.41 mmol), cesium carbonate (0.374 g, 1.15 mmol), andpotassium iodide (0.038 g, 0.23 mmol). The mixture was heated at 100° C.for 1 h, allowed to cool to ambient temperature and concentrated invacuo. The residue was triturated sequentially with water and methanoland further purified by column chromatography and eluted with a 0% to50% gradient of ethyl acetate in dichloromethane to afford3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1-inden]-2′(3′H)-one(0.113 g, 59%) as a colorless solid: mp 217-218° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.41 (d, 1H, J=4.0 Hz), 8.15 (d, J=8.1 Hz, 1H), 7.24 (m, 1H),6.50 (s, 1H), 6.43 (s, 1H), 5.13 (ABq, 2H), 4.75 (ABq, 2H), 4.14-4.09(m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.3, 155.0, 152.6, 148.3, 144.6,143.3, 141.3, 138.2, 132.4, 129.1, 125.1, 123.9, 123.3, 122.1, 120.2,112.3, 109.7, 99.0, 79.7, 64.7, 64.1, 57.7, 44.7; MS (ES+) m/z 464.6(M+1), 466.6 (M+1).

EXAMPLE 11.79 Synthesis of3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one

A mixture of3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one(0.233 g, 0.50 mmol), sodium methanesulfonate (0.071 g, 0.60 mmol),copper iodide (0.010 g, 0.05 mmol), and the sodium salt of L-proline(0.014 g, 0.10 mmol) were combined in dimethyl sulfoxide (1 mL) andheated at 95° C. for 48 h, then stirred at ambient temperature for 30 h.The reaction mixture was diluted with ethyl acetate (50 mL) and washedwith water (100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was triturated from methanol andfurther purified by column chromatography, and eluted with a 0% to 50%gradient of ethyl acetate in dichloromethane to yield3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one(0.103 g, 44%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (d, J=4.2 Hz, 1H), 8.35 (dd, J=8.0, 0.5 Hz, 1H), 7.64(dd, J=7.9, 4.7 Hz, 1H), 7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=7.3Hz, 1H), 7.05-6.99 (m, 2H), 6.50 (s, 1H), 6.39 (s, 1H), 5.50 (ABq, 2H),4.76 (ABq, 2H), 4.19-4.12 (m, 4H), 3.52 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.6, 155.0, 153.7, 153.6, 144.6, 143.4, 138.4, 138.2,135.9, 132.4, 129.1, 124.1, 123.9, 123.3, 122.1, 112.2, 109.8, 99.1,79.6, 64.7, 64.1, 57.7, 44.2, 42.7; MS (ES+) m/z 465.0 (M+1).

EXAMPLE 11.80 Synthesis of2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1-inden]-3′-yl)methyl]pyridine-3-carbonitrile

3′-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,1′-inden]-2′(3′H)-one(0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min undermicrowave irradiation. The reaction mixture was allowed to cool toambient temperature, poured into water (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine(3×20 mL), dried over sodium sulfate, filtered and concentrated invacuo. The resulting residue was subjected to column chromatography, andeluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford2-[1(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile(0.593 g, 29%) as a colorless solid: mp 230-233° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H),7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H),6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74(ABq, 2H), 4.19-4.11 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.3, 158.2,155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4,121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1;MS (ES+) m/z 412.0 (M+1).

EXAMPLE 11.81 Synthesis of(8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.78 and makingnon-critical variations using(8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one,and 3-(difluoromethyl)pyridin-2-yl]methanol hydrochloride to replace(3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride,(8S)-1-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (50%) as a colorless solid: mp 181-182° C.; ¹H NMR (300MHz, DMSO-d₆) δ 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H),7.52-7.50 (m, 1H), 7.52-7.42 (m, 1H), 7.25-7.15 (m, 2H), 7.01 (dd,J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H),5.18 (ABq, 2H), 4.72 (ABq, 2H), 4.19-4.12 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.4, 155.0, 152.9 (t, J_(C-F)=4.3 Hz), 151.4, 144.6, 143.2,138.2, 135.0 (t, J_(C-F)=7.0 Hz), 132.5, 129.1, 128.0 (t, J_(C-F)=22.6Hz), 123.9, 123.5, 123.3, 122.0, 113.8 (t, J_(C-F)=236.6 Hz), 112.3,109.7, 99.1, 79.7, 64.7, 64.1, 57.8, 42.3; MS (ES+) m/z 436.9 (M+1).

EXAMPLE 11.82 Synthesis ofN′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide

To a solution of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(0.40 g, 0.98 mmol) in dimethyl sulfoxide (10 mL) was addedhydroxylamine (50% w/w solution in water, 0.66 mL, 10.7 mmol). Thereaction was stirred at 80° C. for 3 h and allowed to cool to ambienttemperature. Water was added, causing a precipitate to be deposited. Thesolid was collected by filtration and washed with water to affordN′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide(0.40 g, 93%): ¹H NMR (300 MHz, CDCl₃) δ 7.98 (br s, 1H), 7.64 (s, 2H),7.43-7.38 (m, 4H), 7.15-7.11 (m, 2H), 7.01-6.96 (m, 1H), 6.79 (s, 1H),6.67-6.64 (m, 1H), 6.49 (s, 1H), 5.33-5.28 (m, 1H), 4.96-4.58 (m, 3H),4.19-4.16 (m, 4H); MS (ES+) m/z 444.0 (M+1).

EXAMPLE 11.83 Synthesis of1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.27 and makingnon-critical variations usingN′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamideto replaceN′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide,1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: mp 90-95° C. (ethylacetate/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.89-7.87 (m, 2H),7.58-7.53 (m, 2H), 7.25-7.15 (m, 2H), 7.03-6.95 (m, 2H), 6.50 (s, 1H),6.20 (s, 1H), 5.15-4.64 (m, 4H), 4.16-4.07 (m, 4H), 2.62 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 178.1, 177.3, 167.8, 155.2, 144.7, 142.4, 138.4,137.9, 132.2, 130.8, 130.2, 129.3, 127.2, 126.3, 125.5, 124.2, 123.7,121.5, 111.6, 109.9, 99.3, 80.0, 64.7, 64.0, 57.8, 43.1, 12.4; MS (ES+)m/z 467.8 (M+1).

EXAMPLE 11.84 Synthesis of1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile(0.41 g, 1.0 mmol) in dimethylsulfoxide (20 mL) was added hydroxylamine(50% w/w solution in water, 2.0 mL, 33 mmol). The mixture was heated at80° C. for 16 h, allowed to cool to ambient temperature and diluted withwater (50 mL), causing a precipitate to be deposited. The solid wascollected by filtration and combined with pyridine (2.0 mL) and aceticanhydride (0.2 g, 2.0 mmol) in a 10 mL microwave reaction vessel. Themixture was heated at 170° C. for 15 min under microwave irradiation,allowed to cool to ambient temperature and concentrated in vacuo. Theresidue was purified by column chromatography and eluted with a 15% to50% gradient of ethyl acetate in hexanes to afford1′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.52 g, 85%) as a colorless solid: mp 174-175° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆)

8.06-8.00 (m, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.22-7.13 (m, 2H), 7.04-6.97(m, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.50 (s, 1H), 6.23 (s, 1H), 5.12 (d,J=15.8 Hz, 1H), 4.94 (d, J=8.9 Hz, 1H), 4.85 (d, J=15.8 Hz, 1H), 4.66(d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H), 2.63 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.6, 176.6, 168.0, 155.3, 144.7, 141.9, 138.4, 132.2,128.9, 128.0, 127.8, 126.5, 124.0, 123.6, 120.9, 111.5, 109.2, 99.5,80.1, 58.1, 43.9, 12.4; MS (ES+) m/z 467.9 (M+1).

EXAMPLE 11.85 Synthesis of6-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.84 and makingnon-critical variations using2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrileto replace4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile,6-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (61%) as a colorless solid: mp 147-148° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.57 (d, J=4.7 Hz, 1H),7.70-7.61 (m, 2H), 7.56 (d, J=7.9 Hz, 1H), 7.32-7.11 (m, 4H), 7.06-6.98(m, 3H), 6.95-6.86 (m, 1H), 5.20 (d, J=15.8 Hz, 1H), 5.07 (d, J=9.1 Hz,1H), 5.00 (d, J=15.8 Hz, 1H), 4.79 (d, J=9.1 Hz, 1H), 2.63 (s, 1H); ¹³CNMR (75 MHz, CDCl₃) δ 177.0, 176.5, 168.1, 161.1, 155.4, 149.6, 142.2,137.1, 132.2, 131.9, 129.1, 128.5, 124.0, 123.8, 123.7, 122.9, 121.7,120.9, 109.7, 109.3, 80.0, 58.1, 46.2, 12.4; MS (ES+) m/z 410.9 (M+1).

EXAMPLE 11.86 Synthesis of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

A solution of methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate(5.20 g, 11.73 mmol) in tetrahydrofuran (150 mL) and water (80 mL) wascooled to 0° C. under nitrogen and lithium hydroxide (1.13 g, 47.4 mmol)was slowly added. The reaction mixture was stirred at 0° C. for 30 min,allowed to warm to ambient temperature, stirred for an additional 16 hand concentrated in vacuo. The residue was poured into cold (0° C.) 1 Mhydrochloric acid (100 mL), causing a precipitate to be deposited. Themixture was stirred for 2 h at ambient temperature and filtered. Thesolid was washed with water and hexanes to afford3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (5.08 g, 99%) as a colorless solid: mp 254-258° C. (hexanes); ¹HNMR (300 MHz, CDCl₃) δ 8.03-8.00 (m, 2H), 7.59-7.44 (m, 2H), 7.21-7.16(m, 2H), 7.04-7.00 (m, 1H), 6.73-6.71 (m, 1H), 6.50 (s, 1H), 6.31 (s,1H), 5.24-4.60 (m, 5H), 4.15-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)δ177.7, 170.7, 155.2, 144.7, 141.7, 138.5, 136.3, 132.56, 132.3, 130.0,129.7, 129.3, 128.9, 128.6, 124.1, 123.7, 120.9, 111.6, 109.1, 99.5,80.0, 64.5, 63.9, 58.1, 43.6; MS (ES+) m/z 429.7 (M+1).

EXAMPLE 11.87 Synthesis of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid

Following the procedure as described in EXAMPLE 11.12 and makingnon-critical variations using methyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoateto replace methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate,4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid was obtained (89%) as a colorless solid: mp 234-237° C. (water); ¹HNMR (300 MHz, CDCl₃) δ 12.94 (s, 1H), 7.93-7.86 (m, 2H), 7.46-7.40 (m,2H), 7.26-7.19 (m, 1H), 7.18-7.13 (m, 1H), 7.04-6.92 (m, 2H), 6.50 (s,1H), 6.12 (s, 1H), 5.07-4.90 (m, 2H), 4.80 (d, J=9.3 Hz, 1H), 4.65 (d,J=9.3 Hz, 1H), 4.19-4.03 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3,167.5, 155.2, 144.7, 142.6, 141.9, 138.3, 132.1, 130.5, 130.2, 129.3,127.8, 124.2, 123.7, 121.6, 111.6, 109.8, 99.3, 79.9, 64.7, 64.1, 57.7,43.4; MS (ES+) m/z 429.9 (M+1).

EXAMPLE 11.88 Synthesis of1′-[(4-methylpiperazin-1-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

A mixture of5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.35 g, 1.2 mmol), N-methylpiperazine (1.4 mL, 11 mmol), 37% w/waqueous formaldehyde (1.0 mL, 11 mmol) and methanol (2 mL) was heatedfor 2 h. The reaction mixture was poured into water (100 mL), causing aprecipitate to be deposited. The solid was collected by filtration anddissolved in dichloromethane. The resultant solution was dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasdissolved in anhydrous methanol (2 mL) and saturated methanolic hydrogenchloride (5 mL) was added, causing a precipitate to be deposited. Thereaction mixture was diluted with diethyl ether (20 mL) and the solidwas collected by filtration and washed with diethyl ether (2×10 mL) toafford1-[(4-methylpiperazin-1-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.38 g, 65%) as a colorless solid: mp 181° C. (decomp.)(diethyl ether); ¹H NMR (300 MHz, CDCl₃)

11.36 (br s, 1H), 7.37-7.24 (m, 2H), 7.16-7.11 (m, 1H), 7.08-7.00 (m,1H), 6.71 (s, 1H), 6.36 (s, 1H), 5.99 (br s, 4H), 4.82-4.58 (m, 4H),4.45 (t, J=8.7 Hz, 2H), 3.45-2.73 (m, 10H), 2.67 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 179.1, 161.6, 161.0, 143.3, 132.5, 129.0, 124.0, 123.8,120.8, 120.6, 120.0, 110.6, 92.8, 80.6, 72.6, 60.7, 57.4, 52.0, 47.2,47.1, 42.3, 28.9, 11.9; MS (ES+) m/z 392.0 (M+1). Anal. Calcd. forC₂₃H₂₅N₃O₃.2.5HCl: C, 57.24; H, 5.74; N, 8.71. Found: C, 57.23; H, 5.66;N, 8.34.

EXAMPLE 11.89 Synthesis ofN′-hydroxy-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)ethanimidamide

Following the procedure as described in EXAMPLE 11.82 and makingnon-critical variations using(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetonitrileto replace3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile,N′-hydroxy-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)ethanimidamidewas obtained (75%) as a colorless solid: MS (ES+) m/z 367.9 (M+1).

EXAMPLE 11.90 Synthesis of1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 11.27 and makingnon-critical variations usingN′-hydroxy-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)ethanimidamideto replaceN′-hydroxy-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide,1-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%) as a colorless solid: mp 159-160° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃)

7.31-7.23 (m, 1H), 7.22-7.17 (m, 1H), 7.12-7.04 (m, 1H), 6.85 (d, J=7.8Hz, 1H), 6.48 (s, 1H), 6.33 (s, 1H), 5.27 (d, J=16.8 Hz, 1H), 5.08 (d,J=16.8 Hz, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H),4.21-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3, 167.0, 155.2, 144.8,140.7, 138.4, 132.2, 129.0, 124.3, 124.2, 120.7, 115.7 (q, J=274.0 Hz),111.9, 108.5, 99.4, 79.9, 64.5, 63.9, 58.0, 35.6; MS (ES+) m/z 445.9(M+1).

EXAMPLE 11.91 Synthesis of2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide

To a solution of ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate(0.35 g, 0.92 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.15mL, 1.84 mmol) and the solution was heated at reflux for 16 h. Uponbeing allowed to cool to ambient temperature a solid precipitate formed.The solid was filtered and washed with ethanol (2 mL) to afford2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide(0.285 g, 84%) as a colorless solid: MS (ES+) m/z 367.9 (M+1).

EXAMPLE 11.92 Synthesis of1′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide(0.21 g, 0.57 mmol) in pyridine (3.0 mL) at 0° C. was addedtrifluoroacetic anhydride (0.50 mL, 3.59 mmol) The solution was stirredfor 1 h at ambient temperature, poured into 1 M hydrochloric acid (25mL) and the mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with brine (1×50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography and eluted with a 10% to 50% gradientof ethyl acetate in hexanes followed by recrystallization from diethylether to afford1′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(0.05 g, 18%) as a light yellow solid: mp 137-139° C. (diethyl ether);¹H NMR (300 MHz, CDCl₃) δ 7.34-7.17 (m, 2H), 7.14-7.07 (m, 1H), 6.94 (d,J=7.9 Hz, 1H), 6.49 (s, 1H), 6.24 (s, 1H), 5.36-5.17 (ABq, 2H), 4.91 (d,J=9.06 Hz, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.21-4.07 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 177.2, 163.4, 155.2, 144.9, 140.3, 138.5, 131.8, 129.2,124.5, 124.4, 120.3, 111.6, 108.5, 99.5, 79.9, 64.6, 63.9, 58.0, 34.8;MS (ES+) m/z 445.9 (M+1).

EXAMPLE 11.93 Synthesis of1′-(3-aminobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A suspension of1′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(2.7 g, 6.3 mmol), hydrazine hydrate (2.5 g, 50 mmol) and Raney nickel(0.1 g) in methanol (50 mL) was stirred at ambient temperature undernitrogen for 16 h. The reaction mixture was filtered and the filtratewas concentrated in vacuo. Recrystallization of the residue fromchloroform/hexanes (1/1, 20 mL) afforded1-(3-aminobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(1.93 g, 76%) as a colorless solid: MS (ES+) m/z 400.9 (M+1).

EXAMPLE 11.94 Synthesis ofN-{3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]phenyl}methanesulfonamide

A 50 mL round bottom flask was charged with1-(3-aminobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.4 g, 1.0 mmol), pyridine (0.16 g, 2.0 mmol) and dichloromethane (10mL). A solution of methanesulfonyl chloride (0.115 g, 1.0 mmol) indichloromethane (5 mL) was added at 5° C., the reaction mixture wasallowed to warm to ambient temperature and was stirred for 16 h. Thereaction mixture was diluted with dichloromethane (50 mL) and was washedwith water (50 mL) and 1 M hydrochloric acid (50 mL). The organic phasewas dried over magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography and eluted with a0% to 100% gradient of ethyl acetate in dichloromethane affordedN-{3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]phenyl}methanesulfonamide(0.39 g, 82%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.81(s, 1H), 7.32-6.90 (m, 8H), 6.49 (s, 1H), 6.18 (s, 1H), 4.89 (ABq, 2H),4.71 (, 2H), 4.18-4.04 (m, 4H), 2.90 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.2, 155.2, 144.6, 142.7, 139.3, 138.3, 138.0, 132.0, 130.1, 129.2,124.1, 123.5, 122.8, 121.4, 118.7, 117.9, 111.7, 109.9, 99.2, 80.0,64.6, 64.0, 57.7, 43.3; MS (ES+) m/z 478.9 (M+1).

EXAMPLE 11.95 Synthesis of1′-[(1-oxidopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A solution of1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.39 g, 1.0 mmol) and 3-chlorobenzoperoxoic acid (60% w/w, 0.43 g, 1.5mmol) in dichloromethane (20 mL) was stirred at ambient temperature for16 h. The reaction mixture was diluted with dichloromethane (50 mL) andwashed with saturated aqueous sodium bicarbonate (50 mL). The organicphase was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography and eluted witha 5% to 10% gradient of methanol in dichloromethane to afford1-[(1-oxydopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.23 g, 57%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ8.31-8.26 (m, 1H), 7.30-6.94 (m, 7H), 6.48 (s, 1H), 6.23 (s, 1H), 5.24(, 2H), 4.78 (ABq, 2H), 4.20-4.06 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.9, 155.3, 146.0, 144.7, 141.6, 139.8, 138.3, 131.8, 129.2, 125.8,124.9, 124.4, 124.0, 123.9, 120.6, 111.4, 109.4, 99.5, 80.2, 64.5, 63.9,58.1, 39.1; MS (ES+) m/z 402.8 (M+1).

EXAMPLE 11.96 Synthesis of2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid

A 250 mL round-bottom flask was charged with ethyl2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate(2.3 g, 5.0 mmol), lithium hydroxide (0.48 g, 20.0 mmol),tetrahydrofuran (30.mL), water (50.mL) and methanol (30 mL). Thereaction mixture was stirred under nitrogen at reflux for 5 h, allowedto cool to ambient temperature and concentrated in vacuo. The residuewas taken up in water (100 mL) and acidified to pH 1 by the addition of10 M hydrochloric acid, causing a precipitate to be deposited. The solidwas collected by filtration, washed with water and recrystallized fromethanol (50 mL) to afford2-[(2-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid (1.96 g, 91%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆)δ8.57-8.45 (m, 1H), 8.33-8.26 (m, 1H), 7.42 (dd, J=7.82, 4.77 Hz, 1H),7.21-6.83 (m, 4H), 6.49-6.44 (m, 2H), 5.39 (ABq, 2H), 4.72 (ABq, 2H),4.24-4.00 (m, 4H).

EXAMPLE 11.97 Synthesis of1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrobromide

A 50 mL round-bottom Bask was charged with2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid (0.86 g, 2.0 mmol), diphenyl phosphorazidate (0.69 g, 2.5 mmol),triethylamine (0.25 g, 2.5 mmol), tert-butanol (1.48 g, 20.0 mmol) andtoluene (20 mL). The reaction mixture was stirred under nitrogen atreflux for 3 h. The reaction mixture was allowed to cool to ambienttemperature and diluted with ethyl acetate (50 mL). The organic phasewas washed with water (2×50 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with a 0% to 50% gradient of ethyl acetate indichloromethane. The resultant solid was dissolved in dichloromethane(20 mL) and a 30% w/w solution of hydrogen bromide in acetic acid (2.4g, 10.0 mmol) was added. The reaction mixture was stirred at ambienttemperature for 16 h and concentrated in vacuo. The residue wasrecrystallized three times from methanol (20 mL) to afford[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrobromide (0.28 g, 32%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.02-7.72 (m, 3H), 7.54 (dd, J=8.5, 5.5 Hz, 1H), 7.30 (t, J=7.6Hz, 1H), 7.14-7.00 (m, 2H), 6.43 (s, 1H), 6.14 (s, 1H), 5.49 (s, 2H),4.67 (ABq, 2H), 4.17-3.98 (m, 4H); MS (ES+) m/z 402.0 (M+1). Anal.Calc'd for C₂₃H₂₀N₃O₄.1.2 HBr: C, 55.41; H, 4.08; N, 8.43. Found: C,55.84; H, 4.36; N, 8.29.

EXAMPLE 11.98 Synthesis ofN-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide

A 50 mL round-bottom flask was charged with1-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrobromide (0.56 g, 1.0 mmol), methanesulfonyl chloride (0.12 g, 1.1mmol), pyridine (0.25 g, 3.0 mmol) and dichloromethane (20 mL). Thereaction mixture was stirred under nitrogen at ambient temperature for16 h and diluted with dichloromethane (50 mL). The organic phase waswashed with water (2×50 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with a 0% to 100% gradient of ethyl acetate indichloromethane, followed by recrystallization from methanol (10 mL) toaffordN-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide(0.18 g, 38%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 9.64(s, 1H), 8.27 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H),7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.21-7.10 (m, 2H), 6.96 (t, J=7.4 Hz, 1H),6.77 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 5.17 (ABq, 2H), 4.73(ABq, 2H), 4.18-4.05 (m, 4H), 3.14 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.6, 154.9, 151.0, 147.1, 144.5, 143.2, 138.1, 134.5, 132.6, 132.2,132.1, 129.0, 123.8, 123.2, 122.2, 112.3, 109.4, 99.0, 79.6, 64.6, 64.1,57.8, 41.8, 40.6; MS (ES+) m/z 479.9 (M+1).

EXAMPLE 11.99 Synthesis of1-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

To a solution of tert-butyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate(4.10 g, 9.53 mmol) in methanol (10 mL) was added 2 M ethereal hydrogenchloride (20 mL, 40 mmol). The mixture was stirred at ambienttemperature for 5 h and concentrated in vacuo. The residue wastriturated in diethyl ether (50 mL) to afford1-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride (3.50 g, 86%): ¹H NMR (300 MHz, DMSO-d₆) δ9.06-8.50 (br s,2H), 7.39-7.31 (m, 1H), 7.22-7.02 (m, 3H), 6.51 (s, 1H), 6.19 (s, 1H),4.73 (d, J=9.3 Hz, 1H), 4.61 (d, J=9.3 Hz, 1H), 4.23-4.06 (m, 4H),3.73-3.52 (m, 2H), 3.31-3.19 (m, 2H), 2.92-2.70 (m, 2H), 2.16-2.00 (m,1H), 1.87-1.71 (m, 2H), 1.52-1.30 (m, 2H); MS (ES+) m/z 393.0 (M+1).

EXAMPLE 11.100 Synthesis of1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

To a mixture of acetone (0.19 mL, 2.5 mmol) and 1,2-dichloroethane (5.0mL), were added1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride (0.36 g, 0.84 mmol), triethylamine (0.35 mL, 2.5 mmol) andsodium triacetoxyborohydride (0.534 g, 2.52 mmol). The mixture wasstirred at ambient temperature for 16 h and concentrated in vacuo. Theresidue was purified by column chromatography and eluted with ethylacetate/methanol/ammonium hydroxide (20/1/0.2) to afford1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one.To a solution of this compound in methanol (5 mL) was added a 4 Msolution of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) and themixture was stirred at ambient temperature for 30 min and concentratedin vacuo. Sequential trituration of the residue in hexanes and diethylether afforded{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride (0.21 g, 53%) as an off-white solid: mp 213-216° C.; ¹HNMR (300 MHz, DMSO-d₆) δ10.02-9.80 (br s, 1H), 7.40-7.02 (m, 4H), 6.51(s, 1H), 6.18 (s, 1H), 4.74 (d, J=9.3 Hz, 1H), 4.62 (d, J=9.3 Hz, 1H),4.23-4.06 (m, 4H), 3.73-3.21 (m, 4H), 3.00-2.78 (m, 2H), 2.20-1.52 (m,5H), 1.32-1.12 (m, 7H); ¹³C NMR (75 MHz, DMSO-d₆) δ176.8, 154.7, 144.0,142.5, 137.7, 131.6, 128.7, 123.5, 122.8, 121.0, 111.1, 109.2, 98.6,79.7, 64.1, 63.5, 57.1, 56.7, 47.1, 44.2, 32.1, 26.6, 26.4, 16.1; MS(ES+) m/z 435.1 (M+1).

EXAMPLE 11.101 Synthesis of1-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure described in EXAMPLE 11.100 and makingnon-critical variations using 37% w/w aqueous formaldehyde to replaceacetone, and tetrahydrofuran to replace dichloromethane,1-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride was obtained (60%) as a colorless solid: mp1 86-202° C.;¹H NMR (300 MHz, DMSO-d₅) δ 10.07-10.03 (br s, 1H), 7.48-6.94 (m, 4H),6.46 (s, 1H), 6.15 (s, 1H), 4.80-4.50 (m, 2H), 4.25-4.00 (m, 4H),3.74-2.50 (m, 9H), 2.10-1.38 (m, 5H); MS (ES+) m/z 407.1 (M+1).

EXAMPLE 11.102 Synthesis of1-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′1-1)-one

1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(3.36 g, 6.93 mmol) was suspended in methanol (20 mL) and ethyl acetate(20 mL) in a Parr bottle, and palladium on carbon (20% w/w, 0.50 g) wasadded. The mixture was shaken in a Parr hydrogenation apparatus at 50psi and at ambient temperature for 16 h. The reaction mixture wasfiltered through a pad of diatomaceous earth and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyand eluted with ethyl acetate/methanol/7 N methanolic ammonia (10:1:0.1)to afford1-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(1.7 g, 62%) as a colorless foam: mp 154-159° C.; ¹H NMR (mixture ofdiasteroisomers, 300 MHz, CDCl₃) δ 7.33-7.24 (m, 1H), 7.17-7.00 (m, 3H),6.49 (s, 0.5H), 6.48 (s, 0.5H), 6.24 (s, 0.5H), 6.21 (s, 0.5H),4.91-4.85 (m, 1H), 4.66-4.60 (m, 1H), 4.22-4.08 (m, 4H), 3.94-3.51 (m,5H), 3.00-2.61 (m, 4H); MS (ES+) m/z 395.1 (M+1).

EXAMPLE 11.103 Synthesis of1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.100 and makingnon-critical variations using1-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (88%) as a colorless solid: mp 102-125° C.; ¹H NMR (mixtureof diasteroisomers, 300 MHz, CDCl₃) δ 7.33-7.26 (m, 1H), 7.20-7.00 (m,3H), 6.49 (s, 0.5H), 6.48 (s, 0.5H), 6.26 (s, 0.5H), 6.20 (s, 0.5H),4.88 (d, J=9.0 Hz, 1H), 4.67-4.61 (m, 1H), 4.21-4.07 (m, 4H), 4.00-3.56(m, 5H), 2.85-2.56 (m, 3H), 2.35-2.05 (m, 2H), 1.02 (d, J=6.6 Hz, 6H);MS (ES+) m/z 437.2 (M+1).

EXAMPLE 11.104 Synthesis of1-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.100 and makingnon-critical variations using 37% w/w aqueous formaldehyde to replaceacetone, tetrahydrofuran to replace dichloromethane, and1-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (91%) as a colorless solid: mp 102-112° C.; ¹H NMR (mixtureof diasteroisomers, 300 MHz, CDCl₃) δ 7.33-7.26 (m, 1H), 7.17-7.00 (m,3H), 6.48 (s, 1H), 6.26 (s, 0.5H), 6.21 (s, 0.5H), 4.91-4.85 (m, 1H),4.66-4.60 (m, 1H), 4.22-4.08 (m, 4H), 3.94-3.58 (m, 5H), 2.77 (d, J=11.7Hz, 1H), 2.61 (d, J=11.7 Hz, 1H), 2.28 (s, 3H), 2.18-2.06 (m, 1H),1.99-1.89 (m, 1H); MS (ES+) m/z 409.2 (M+1).

EXAMPLE 11.105 Synthesis of(8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.102 and makingnon-critical variations using(8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,(8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (56%): MS (ES+) m/z 395.1 (M+1).

EXAMPLE 11.106 Synthesis of(8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.100 and makingnon-critical variations using 37% w/w aqueous formaldehyde to replaceacetone, tetrahydrofuran to replace 1,2-dichloroethane and(8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride,(8S)-1-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (68%) as a colorless solid: mp 85-90° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.27 (d, J=7.5 Hz, 1H), 7.15-6.98 (m, 3H), 6.47 (s, 1H), 6.20(s, 1H), 4.86 (d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.19-4.05 (m,4H), 3.92-3.56 (m, 5H), 2.76 (d, J=11.4 Hz, 1H), 2.60 (d, J=11.4 Hz,1H), 2.26 (s, 3H), 2.17-2.05 (m, 1H), 1.97-1.87 (m, 1H); ¹³C NMR (300MHz, CDCl₃) δ177.6, 155.1, 144.5, 142.6, 138.2, 132.0, 128.7, 123.6,123.2, 121.0, 111.4, 109.4, 99.2, 80.0, 73.5, 66.7, 64.4, 63.8, 58.1,57.8, 54.6, 46.3, 43.1; MS (ES+) m/z 409.2 (M+1).

EXAMPLE 11.107 Synthesis of1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one

To a cooled (0° C.) solution of 3-trifluoromethyl-pyridin-2-yl)methanolhydrochloride (0.24 g, 1.1 mmol) in dichloromethane (10.mL) was addedN,N-dimethylformamide (2 drops, catalytic amount) and thionyl chloride(0.15 mL). The solution was stirred for 16 h at ambient temperature andconcentrated in vacuo. The residue was dissolved inN,N-dimethylformamide (10 mL) and cesium carbonate (0.98 g, 3.0 mmol),potassium iodide (100 mg) andspiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one (0.28 g,1.0 mmol) were added. The reaction was heated at 60° C. for 3 h, allowedto cool to ambient temperature and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography and eluted with a 15% to 30% gradient of ethyl acetate inhexanes to afford1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one(0.28 g, 64%) as a colorless solid: mp 212-215° C.; ¹H NMR (300 MHz,CDCl₃) δ8.62 (d, J=4.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.82 (dd, J=9.6,0.9 Hz, 1H), 7.34-7.27 (m, 2H), 7.23-7.16 (m, 2H), 7.01 (dd, J=7.5, 7.5Hz, 1H), 6.71 (d, J=7.8 Hz, 1H), 5.46 (d, J=17.4 Hz, 1H), 5.30 (d, J=9.3Hz, 1H), 5.21 (d, J=17.4 Hz, 1H), 5.01 (d, J=9.3 Hz, 1H); ¹³C NMR (75MHz, CDCl₃) δ 176.9, 163.2, 152.5, 152.2, 148.4, 145.0, 142.8, 134.1 (q,J=5.2 Hz), 129.8, 129.6, 125.6, 124.5, 124.1, 123.7, 123.4, 122.1,121.9, 121.8, 119.3, 82.4, 57.3, 42.7 (q, J=3.3 Hz); MS (ES+) m/z 439.1(M+1).

EXAMPLE 11.108 Synthesis of6-chloro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.107 and makingnon-critical variations using6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-oneto replacespiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one,chloro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-41′H)-onewas obtained (70%) as a colorless solid: mp 273-275° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.70 (d, J=4.5 Hz, 1H), 8.26-8.21 (m, 1H), 7.58-7.51 (m,1H), 7.26-7.18 (m, 2H), 7.08-6.98 (m, 1H), 6.94-6.88 (m, 2H), 5.24 (ABq,2H), 4.79 (ABq, 2H), 4.14-3.96 (m, 4H); MS (ES+) m/z 489.2 (M+1), 491.2(M+1).

EXAMPLE 11.109 Synthesis of1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.107 and makingnon-critical variations using2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one toreplace spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one,1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 245-247° C.; ¹H NMR (300MHz, CDCl₃) δ 8.58 (d, J=4.5 Hz, 1H), 7.98 (d, J=4.5 Hz, 1H), 7.34-7.26(m, 1H), 7.20-7.12 (m, 2H), 7.04-6.97 (m, 1H), 6.74 (d, J=8.7 Hz, 1H),6.63-6.58 (m, 1H), 6.46 (d, J=8.7 Hz, 1H), 5.56 (d, J=17.4 Hz, 1H), 5.06(d, J=16.8 Hz, 1H), 4.97 (d, J=8.7 Hz, 1H), 4.70 (d, J=8.7 Hz, 1H),4.17-3.92 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 156.2, 152.9, 152.4,152.3, 142.3, 140.0, 138.6, 138.1, 134.1 (q, J=5.3 Hz), 131.7, 128.3,124.5, 123.5, 122.9, 122.0, 118.0, 115.6, 108.4, 102.2, 81.8, 64.7,63.9, 57.2, 42.6 (q, J=3.1 Hz); MS (ES+) m/z 455.2 (M+1).

EXAMPLE 11.110 Synthesis of1-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 11.107 and makingnon-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-41H)-one toreplace spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-oneand (5-(difluoromethyl)furan-2-yl)methanol to replace3-trifluoromethyl-pyridin-2-yl)methanol hydrochloride,1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (35%) as a colorless solid: mp 173-175° C.; ¹H NMR (300MHz, CDCl₃) δ 7.33-7.25 (m, 1H), 7.21-7.14 (m, 1H), 7.11-6.96 (m, 2H),6.63-6.58 (m, 1H), 6.57 (t, J_(H-F)=54.3 Hz, 1H), 6.50 (s, 1H),6.37-6.34 (m, 1H), 6.20 (s, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.94-4.83 (m,2H), 4.65 (d, J=9.0 Hz, 1H), 4.23-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)δ177.1, 155.2, 151.1 (t, J_(C-F)=2.2 Hz), 146.5, 144.6, 141.5, 138.3,132.1, 128.9, 123.9, 123.7, 120.8, 111.5, 111.3 (t, J_(C-F)=4.1 Hz),109.2, 108.9, 108.2 (t, J_(C-F)=233.6 Hz), 99.4, 80.0, 64.5, 63.9, 57.9,37.0; MS (ES+) m/z 425.9 (M+1).

EXAMPLE 11.111 Synthesis of5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a solution of tert-butyl4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate(0.47 g, 1.01 mmol) in anhydrous methanol (8 mL) and anhydrousdichloromethane (3 mL) was added a 4.0 M solution of hydrogen chloridein 1,4-dioxane (4.0 mL, 16 mmol) and the reaction mixture was stirred atambient temperature for 16 h. Anhydrous diethyl ether (30 mL) was addedto the reaction mixture, causing a precipitate to be deposited.Trituration of the resultant solid in diethyl ether (2×30 mL) afforded5,6-difluoro-1-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.36 g, 88%) as a colorless solid: mp>200° C.; ¹H NMR(300 MHz, CD₃OD) δ 7.40 (ddd, J=7.6, 7.6, 1.4 Hz, 1H), 7.24-7.12 (m,3H), 6.92 (dd, J=10.7, 6.4 Hz, 1H), 6.69 (dd, J=9.5, 8.0 Hz, 1H), 4.91(d, J=9.4 Hz, 1H), 4.76 (d, J=9.4 Hz, 1H), 3.85-3.65 (m, 2H), 3.47-3.37(m, 2H), 3.05-2.93 (m, 2H), 2.32-2.16 (m, 1H), 2.05-1.92 (m, 2H),1.64-1.46 (m, 2H); ¹³C NMR (75 MHz, CD₃OD) δ 179.3, 158.7 (d,J_(C-F)=13.0 Hz), 152.6 (dd, J_(C-F)=246.7, 14.5 Hz), 146.9 (dd,J_(C-F)=239.8, 14.0 Hz), 144.0, 132.7, 130.7, 125.7 (dd, J_(C-F)=6.5,3.2 Hz), 125.1, 112.9 (d, J_(C-F)=22.2 Hz), 110.7, 100.9 (d,J_(C-F)=22.7 Hz), 82.2, 59.4, 46.1, 44.8, 33.8, 27.8; MS (ES+) m/z 371.3(M+1). Anal. Calcd for C₂₁H₂₀F₂N₂O₂.HCl: C, 61.99; H, 5.20; N, 6.89.Found: C, 61.73; H, 5.28; N, 7.03.

EXAMPLE 11.112 Synthesis of5,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a solution of5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride (0.240 g, 0.590 mmol) in tetrahydrofuran (5 mL) was addedtriethylamine (0.08 mL, 1.18 mmol), formaldehyde (37% w/w in water, 0.18mL, 2.24 mmol), sodium triacetoxyborohydride (0.375 g, 1.77 mmol), andacetic acid (3 drops). The reaction mixture was stirred at ambienttemperature for 3.5 h and concentrated in vacuo. Water (10 mL) was addedto the residue and the mixture was extracted with dichloromethane (3×75mL). The combined organic extracts were dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with dichloromethane/methanol/ammoniumhydroxide (10/1/0.2) to afford5,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2(1′H)-onehydrochloride (0.205 g, 90%) as a colorless solid: mp 162-164° C.; ¹HNMR (300 MHz, CDCl₃) δ7.40 (dd, J=7.5, 7.5 Hz, 1H), 7.23-7.12 (m, 3H),6.92 (dd, J=10.7, 6.4 Hz, 1H), 6.69 (dd, J=9.4, 8.0 Hz, 1H), 4.91 (d,J=9.4 Hz, 1H), 4.76 (d, J=9.4 Hz, 1H), 3.76 (t, J=7.0 Hz, 2H), 3.55-3.48(m, 2H), 3.02-2.92 (m, 2H), 2.86 (s, 3H), 2.30-1.92 (m, 3H), 1.65-1.56(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 179.0, 158.5 (d, J_(C-F)=10.3 Hz),152.3 (d, J_(C-F)=247.1 Hz), 146.7 (d, J_(C-F)=238.3 Hz), 143.9, 132.5,131.1, 125.4, 125.0, 113.6 (d, J_(C-F)=19.8 Hz), 112.3, 100.8 (d,J_(C-F)=22.2 Hz), 83.1, 59.0, 57.0, 56.7, 46.7, 34.0, 29.6, 29.5; MS(ES+) m/z 385.3 (M+1). Anal. Calcd for C₂₂H₂₂F₂N₂O₂.2.4HCl: C, 55.99; H,5.21; N, 5.94. Found: C, 55.75; H, 5.19; N, 5.97.

EXAMPLE 12 Synthesis ofN-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

A suspension of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (2.13 g, 5.1 mmol) and N,N-dimethylformamide (0.001 mL, catalyticamount) in anhydrous dichloromethane (30 mL) was treated with oxalylchloride (4.50 mL, 5.1 mmol). The reaction mixture was stirred atambient temperature for 3 h. The crude product was concentrated in vacuoto afford3-(((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoylchloride as a light yellow solid. A solution of3-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indoline]-1′-yl)methyl)benzoylchloride (0.27 g, 0.6 mmol), cyclohexanemethylamine (0.17 mL, 1.3 mmol),triethylamine (0.44 mL, 3.2 mmol), and 4-(dimethylamino)pyridine (0.005g, catalytic amount) in anhydrous dichloromethane (5 mL), was stirred atambient temperature for 20 h under nitrogen. The reaction mixture wasdiluted with dichloromethane (10 mL) and aqueous citric acid (10 mL) andthe phases were separated. The organic phase was washed with water (10mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography with ethyl acetate in hexanes (0% to 100% gradient) toaffordN-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.33 g, 65%) as a colourless solid: ¹H NMR (300 MHz, CDCl₃) δ7.80 (s,1H), 7.63 (d, J=7.4 Hz, 1H), 7.48-7.37 (m, 2H), 7.23-7.15 (m, 2H),7.08-7.00 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.43 (s, 1H),6.19-6.09 (m, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91(d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H),3.33-3.23 (m, 2H), 3.07-2.95 (m, 2H), 1.82-1.64 (m, 5H), 1.34-1.13 (m,4H), 1.07-0.86 (m, 2H); MS (ES+) m/z 509.0 (M+1).

EXAMPLE 12.1 Synthesis ofN-(2-methoxyethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-methoxyethylamine to replacecyclohexanemethylamine,N-(2-methoxyethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (67%) as a colorless solid: mp 72-73° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.83, (s, 1H), 7.65 (d, J=6.3 Hz,1H), 7.46-7.36 (m, 2H), 7.22-7.17 (m, 2H), 7.06-7.01 (m, 1H), 6.78 (d,J=7.7 Hz, 1H), 6.56-6.51 (m, 1H), 6.51 (s, 1H), 6.43 (s, 1H), 5.08 (d,J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H), 4.72(d, J=9.0 Hz, 1H), 4.57-4.51 (m, 2H), 3.67-3.62 (m, 2H), 3.57-3.54 (m,2H), 3.38 (s, 3H), 3.05-2.98 (m, 2H); MS (ES+) m/z 471.0 (M+1).

EXAMPLE 12.2 Synthesis ofN-hexyl-N-methyl-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using N-hexylmethylamine to replacecyclohexanemethylamine,N-hexyl-N-methyl-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (80%) as a colorless solid: mp 73-74° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.36 (m, 3H), 7.31-7.26 (m,1H), 7.22-7.16 (m, 2H), 7.05-7.00 (m, 1H), 6.82-6.75 (m, 1H), 6.49 (s,1H), 6.43 (s, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.86(d, J=15.7 Hz, 1H), 4.71 (d, J=8.6 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H),3.19-3.12 (m, 1H), 3.05-2.84 (m, 5H), 1.64 (m, 2H), 1.56-1.47 (m, 1H),1.38-1.34 (m, 3H), 1.22-1.04 (m, 3H), 0.96-0.79 (m, 3H); MS (ES+) m/z511.1 (M+1).

EXAMPLE 12.3 Synthesis ofN-(2-ethylbutyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-ethyl-n-butylamine to replacecyclohexanemethylamine,N-(2-ethylbutyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (40%) as a colorless solid: mp 105-106° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.80 (s, 1H), 7.62 (d, J=7.3 Hz, 1H),7.47-7.38 (m, 2H), 7.23-7.15 (m, 2H), 7.06-7.00 (m, 1H), 6.79 (d, J=7.8Hz, 1H), 6.51 (s, 1H), 6.43 (s, 1H), 6.10-6.01 (m, 1H), 5.09 (d, J=15.9Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.91 (d, J=15.9 Hz, 1H), 4.72 (d, J=9.0Hz, 1H), 4.55 (t, J=8.7 Hz, 2H), 3.44-3.38 (m, 2H), 3.05-2.96 (m, 2H),1.55-1.46 (m, 1H), 1.42-1.32 (m, 4H), 0.93 (t, J=7.3 Hz, 6H); MS (ES+)m/z 497.0 (M+1).

EXAMPLE 12.4 Synthesis ofN-(2,4-dimethylphenyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2,4-dimethylaniline to replacecyclohexanemethylamine,N-(2,4-dimethylphenyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (57%) as a colorless solid: mp 234-235° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.89 (s, 1H), 7.77 (d, J=7.6 Hz, 2H),7.57-7.45 (m, 3H), 7.24-7.18 (m, 2H), 7.07 (s, 1H), 7.06-7.02 (m, 2H),6.82 (d, J=7.8 Hz, 1H), 6.47 (s, 1H), 6.43 (s, 1H), 5.19 (d, J=15.7 Hz,1H), 5.00 (d, J=9.0 Hz, 1H), 4.88 (d, J=15.7 Hz, 1H), 4.72 (d, J=9.0 Hz,1H), 4.53-4.35 (m, 2H), 2.91-2.84 (m, 2H), 2.31 (s, 3H), 2.20 (s, 3H);MS (ES+) m/z 516.1 (M+1).

EXAMPLE 12.5 Synthesis of3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-phenylpropyl)benzamide

Following the procedure described in EXAMPLE 12 and making non-criticalvariations using 2-phenylpropan-1-amine to replacecyclohexanemethylamine,3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-phenylpropyl)benzamidewas obtained (82%) as a colorless solid: ¹H NMR (300 MHz, (CD₃)₂CO)δ7.88 (s, 1H), 7.83-7.73 (m, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.54 (d, J=7.7Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.14 (m, 7H), 7.09-7.01 (m, 1H), 6.93(d, J=7.8 Hz, 1H), 6.63 (s, 1H), 6.34 (s, 1H), 5.15 (d, J=15.9 Hz, 1H),4.94 (d, J=9.2 Hz, 1H), 4.92 (d, J=15.9 Hz, 1H), 4.76 (d, J=9.1 Hz, 1H),4.53 (t, J=8.7 Hz, 2H), 3.58-3.50 (m, 2H), 3.19-2.93 (m, 3H), 1.28 (d,J=7.0 Hz, 3H); MS (ES+) m/z 531.1 (M+1).

EXAMPLE 12.6 Synthesis ofN-[(1S)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using (S)-(+)-1-cyclohexylethylamine to replacecyclohexanemethylamine,N-[(1S)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (87%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.80(d, J=6.1, 1H), 7.64-7.57 (m, 1H), 7.46-7.36 (m, 2H), 7.23-7.15 (m, 2H),7.07-7.00 (m, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.51 (s, 1H), 6.43 (s, 1H),5.89 (d, J=9.0 Hz, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H),4.92 (d, J=15.7 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H),3.06-2.95 (m, 2H), 1.85-1.61 (m, 5H), 1.58 (s, 3H), 1.49-1.35 (m, 1H),1.19-0.97 (m, 6H); MS (ES+) m/z 523.1 (M+1).

EXAMPLE 12.7 Synthesis ofN-[(1R)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using (R)-(−)-1-cyclohexylethylamine to replacecyclohexanemethylamine,N-[(1R)-1-cyclohexylethyl]-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (60%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.80(d, J=6.1, 1H), 7.64-7.57 (m, 1H), 7.46-7.36 (m, 2H), 7.23-7.15 (m, 2H),7.07-7.00 (m, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.51 (s, 1H), 6.43 (s, 1H),5.89 (d, J=9.0 Hz, 1H), 5.08 (d, J=15.7 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H),4.92 (d, J=15.7 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.55 (t, J=8.6 Hz, 2H),3.06-2.95 (m, 2H), 1.85-1.61 (m, 5H), 1.58 (s, 3H), 1.49-1.35 (m, 1H),1.19-0.97 (m, 6H); MS (ES+) m/z 523.1 (M+1).

EXAMPLE 12.8 Synthesis ofN-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 4-ethylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (87%) as a colorless solid: mp>230° C.; ¹H NMR (300 MHz,DMSO-d₆) δ10.50 (s, 1H), 7.68-7.55 (m, 3H), 7.49-7.35 (m, 2H), 7.23-7.10(m, 5H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.51 (s,1H), 6.39 (s, 1H), 5.15-4.99 (m, 2H), 4.83 (d, J=8.9 Hz, 1H), 4.68 (d,J=8.9 Hz, 1H), 4.46 (t, J=8.7 Hz, 2H), 2.99-2.85 (m, 2H), 2.54 (q, J=7.5Hz, 2H), 1.14 (t, J=7.5 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.8,167.4, 161.6, 161.2, 142.8, 139.7, 137.2, 136.7, 134.4, 132.7, 130.8,129.1, 129.3, 127.8, 127.1, 124.1, 123.6, 120.9, 120.4, 120.3, 119.6,109.7, 92.9, 80.4, 72.6, 57.4, 41.5, 28.8, 28.1, 16.3; MS (ES+) m/z517.2 (M+1).

EXAMPLE 12.9 Synthesis ofN-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-ethylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[4(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (95%) as a colorless solid: mp 184-186° C.; ¹H NMR (300MHz, DMSO-d₆) δ10.06 (s, 1H), 7.69-7.61 (m, 1H), 7.50-7.34 (m, 3H),7.31-7.13 (m, 6H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.90 (d, J=7.8 Hz, 1H),6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H),4.72 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H),2.68 (q, J=7.5 Hz, 2H), 1.16 (t, J=7.5 Hz, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.9, 168.1, 161.6, 161.2, 142.8, 139.8, 136.4, 135.8,134.5, 132.7, 130.8, 129.1, 129.0, 128.3, 127.9, 127.8, 127.0, 126.9,126.5, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 57.5,41.4, 28.8, 24.5, 14.8; MS (ES+) m/z 517.2 (M+1).

EXAMPLE 12.10 Synthesis ofN-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2,4-dimethylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (90%) as a colorless solid: mp 207-208° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.95 (s, 1H), 7.69-7.61 (m, 1H), 7.49-7.34 (m, 2H),7.31-7.13 (m, 4H), 7.09-6.95 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.53 (s,1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.71 (d,J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.25 (s,6H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.9, 167.7, 161.6, 161.2, 142.8,136.6, 135.6, 134.4, 133.9, 133.5, 132.7, 131.3, 130.8, 129.1, 128.4,127.8, 126.9, 126.7, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9,80.4, 72.6, 65.4, 57.5, 41.4, 28.8, 21.0, 18.4, 15.6; MS (ES+) m/z 517.2(M+1).

EXAMPLE 12.11 Synthesis ofN-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using o-anisidine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (84%) as a colorless solid: mp 172-174° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.66 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.0 Hz,1H), 7.49-7.32 (m, 2H), 7.24-6.86 (m, 8H), 6.52 (s, 1H), 6.40 (s, 1H),5.19-5.00 (m, 2H), 4.86 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 3.79(s, 3H), 2.93 (t, J=8.7 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.9,167.6, 161.6, 161.2, 152.1, 142.8, 136.5, 134.4, 132.6, 130.8, 129.1,128.2, 127.8, 127.1, 126.8, 126.5, 124.9, 124.1, 123.6, 120.9, 120.7,120.4, 119.6, 112.0, 109.7, 92.9, 80.4, 72.6, 57.4, 56.2, 41.4, 28.8; MS(ES+) m/z 519.2 (M+1).

EXAMPLE 12.12 Synthesis ofN-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-fluoroaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (57%) as a colorless solid: mp 195-197° C.; ¹H NMR (300MHz, DMSO-d₆) δ10.37 (s, 1H), 7.75-7.59 (m, 2H), 7.51-7.35 (m, 2H),7.34-7.11 (m, 6H), 7.00 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H),6.52 (s, 1H), 6.40 (s, 1H), 5.19-5.00 (m, 2H), 4.85 (d, J=9.4 Hz, 1H),4.70 (d, J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 2H);¹³C NMR (75 MHz, DMSO-d₆) δ177.8, 161.6, 161.2, 142.8, 135.8, 134.6,132.7, 131.1, 129.1, 128.6, 127.8, 127.4, 127.3, 127.0, 126.0, 125.8,124.8, 124.7, 124.2, 123.6, 120.9, 120.4, 119.6, 116.4, 116.2, 109.7,92.9, 80.5, 72.6, 57.5, 41.4, 28.8; MS (ES+) m/z 529.2 (M+23).

EXAMPLE 12.13 Synthesis ofN-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 3-chloroaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (81%) as a colorless solid: mp>230° C.; ¹H NMR (300 MHz,DMSO-d₆) δ10.71 (s, 1H), 7.96-7.90 (m, 1H), 7.65-7.57 (m, 2H), 7.52-7.31(m, 3H), 7.26-7.10 (m, 4H), 6.99 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.16-4.99 (m, 2H), 4.82 (d, J=9.4Hz, 1H), 4.67 (d, J=9.4 Hz, 1H), 4.46 (t, J=8.8 Hz, 2H), 3.01-2.83 (m,2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.8, 167.8, 161.6, 161.2, 142.8,140.9, 136.1, 134.5, 133.5, 132.7, 131.1, 130.8, 129.1, 128.5, 127.9,127.4, 124.1, 123.9, 123.6, 120.9, 120.3, 119.8, 119.6, 118.7, 109.8,92.9, 80.4, 72.6, 57.4, 41.7, 28.8; MS (ES+) m/z 523.1 (M+1).

EXAMPLE 12.14 Synthesis ofN-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 3-fluoro-2-methylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (84%) as a colorless solid: mp>230° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.23 (s, 1H), 7.68 (d, J=6.6 Hz, 1H), 7.51-7.37 (m, 2H),7.33-7.13 (m, 5H), 7.11-6.97 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.58 (s,1H), 6.39 (s, 1H), 5.16-5.02 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.70 (d,J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 1H), 2.21-2.14(m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.8, 167.8, 162.8, 161.6, 161.2,159.6, 142.8, 138.3, 138.2, 136.1, 134.6, 132.7, 131.0, 129.1, 128.5,127.9, 127.1, 127.0, 126.9, 124.2, 123.6, 122.7, 121.1, 126.9, 120.3,119.6, 113.0, 112.7, 109.7, 92.9, 80.4, 72.6, 65.4, 57.4, 41.4, 28.8,15.6, 10.4, 10.3; MS (ES+) m/z 543.1 (M+23).

EXAMPLE 12.15 Synthesis ofN-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using heptylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (75%) as a colorless solid: mp 196-198° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.53 (t, J=5.5 Hz, 1H), 7.46-7.27 (m, 3H), 7.23-7.06 (m,3H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.51 (s, 1H),6.40 (s, 1H), 5.10=-4.92 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.71 (d, J=9.4Hz, 1H), 4.55-4.39 (m, 2H), 3.23 (q, J=6.8 Hz, 2H), 3.03-2.84 (m, 2H),1.59-1.44 (m, 2H), 1.38-1.14 (m, 8H), 0.81 (t, J=6.6 Hz, 1H); ¹³C NMR(75 MHz, DMSO-d₆) δ177.8, 168.7, 161.6, 161.2, 142.8, 136.9, 134.1,132.6, 130.4, 129.1, 128.1, 127.8, 126.8, 124.1, 123.6, 120.9, 120.3,119.6, 109.6, 92.9, 80.4, 72.6, 57.4, 41.3, 31.7, 29.4, 28.9, 28.8,26.9, 22.5, 14.4; MS (ES+) m/z 511.2 (M+1).

EXAMPLE 12.16 Synthesis ofN-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-chlorobenzylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (88%) as a colorless solid: mp 148-150° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.12 (t, J=5.8 Hz, 1H), 7.57 (dd, J=7.2, 1.5 Hz, 1H),7.51-7.24 (m, 6H), 7.23-7.11 (m, 3H), 7.00 (dd, J=7.2, 7.2 Hz, 1H), 6.86(d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.15-4.95 (m, 2H), 4.86(d, J=9.4 Hz, 1H), 4.71 (d, J=9.4 Hz, 1H), 4.57-4.41 (m, 2H), 3.01-2.88(m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.8, 169.0, 161.6, 161.2, 142.8,136.6, 135.9, 134.6, 132.6, 132.5, 130.8, 129.7, 129.4, 129.2, 129.1,128.4, 127.7, 127.0, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9,80.4, 72.6, 57.4, 41.4, 41.1, 28.8; MS (ES+) m/z 537.2 (M+1).

EXAMPLE 12.17 Synthesis of1′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using piperidine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,1′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (88%) as a colorless solid: mp 168-170° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.42-7.10 (m, 6H), 6.99 (dd, J=7.5, 7.5 Hz, 1H),6.65-6.44 (br, 1H), 6.39 (s, 1H), 4.90-4.64 (m, 4H), 4.54-4.39 (m, 2H),3.77-3.42 (br, 2H), 3.21-3.07 (m, 2H), 2.94 (t, J=8.2, 1.5 Hz, 1H),1.66-1.33 (m, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.7, 167.9, 161.6,161.2, 142.7, 136.4, 132.6, 129.6, 129.1, 128.1, 126.6, 124.1, 123.5,120.9, 120.3, 109.8, 92.9, 80.5, 72.6, 65.4, 57.4, 47.9, 42.3, 41.4,28.8, 26.4, 25.7, 24.4, 15.6; MS (ES+) m/z 481.2 (M+1).

EXAMPLE 12.18 Synthesis ofN-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using butylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (77%) as a colorless solid: mp 176-178° C.; ¹H NMR (300MHz, CDCl₃) δ7.48-7.41 (m, 1H), 7.37-7.14 (m, 6H), 7.09-6.99 (m, 3H),6.55-6.37 (m, 3H), 5.25-5.07 (m, 2H), 4.94 (d, J=9.0 Hz, 1H), 4.70 (d,J=9.0 Hz, 1H), 4.52 (t, J=8.2 Hz, 2H), 3.47 (q, J=6.6 Hz, 2H), 2.98 (t,J=8.7 Hz, 2H), 1.67-1.55 (m, 2H), 1.50-1.35 (m, 2H), 0.95 (t, J=6.6 Hz,1H); MS (ES+) m/z 491.1 (M+23).

EXAMPLE 12.19 Synthesis ofN-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using m-toluidine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (81%) as a colorless solid: mp 229-231° C.; ¹H NMR (300MHz, CDCl₃) δ8.85 (s, 1H), 7.64-7.55 (m, 2H), 7.49-7.42 (m, 1H),7.40-7.33 (m, 2H), 7.32-7.16 (m, 4H), 7.11-7.03 (m, 2H), 6.96 (d, J=7.6Hz, 1H), 6.40 (s, 2H), 5.22-5.05 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.67(d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.35(s, 3H); MS (ES+) m/z 525.11 (M+23).

EXAMPLE 12.20 Synthesis ofN-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-fluoro-5-methylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (77%) as a colorless solid: mp 214-216° C.; ¹H NMR (300MHz, CDCl₃) δ 8.25-8.06 (m, 2H), 7.65-7.57 (m, 1H), 7.47-7.33 (m, 2H),7.33-7.26 (m, 1H), 7.22-7.12 (m, 2H), 7.07-6.86 (m, 4H), 6.46 (s, 1H),6.40 (s, 1H), 5.27 (s, 2H), 4.95 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz,1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.36 (s, 3H); MS(ES+) m/z 543.1 (M+23).

EXAMPLE 12.21 Synthesis ofN-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2,3-dimethylaniline to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (87%) as a colorless solid: mp>230° C.; ¹H NMR (300 MHz,CDCl₃) δ7.98 (s, 1H), 7.69-7.53 (m, 2H), 7.46-7.33 (m, 2H), 7.33-7.11(m, 6H), 7.11-6.99 (m, 3H), 6.45 (s, 1H), 6.40 (s, 1H), 5.34-5.17 (m,2H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz,2H), 2.96 (t, J=8.5 Hz, 2H), 2.32 (s, 3H), 2.22 (s, 3H); MS (ES+) m/z539.1 (M+23).

EXAMPLE 12.22 Synthesis ofN-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-(4-methoxyphenyl)ethylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (85%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.39-7.13 (m, 8H), 7.08-6.95 (m, 2H), 6.86-6.78 (m, 2H), 6.52-6.39 (m,3H), 5.10-4.90 (m, 3H), 4.70 (d, J=9.0 Hz, 1H), 3.81-3.62 (m, 5H), 2.98(t, J=8.7 Hz, 2H), 2.90 (t, J=8.7 Hz, 2H); MS (ES+) m/z 569.2 (M+23).

EXAMPLE 12.23 Synthesis ofN-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 3-chlorobenzylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (84%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.52-7.47 (m, 1H), 7.39-7.15 (m, 9H), 7.09-7.00 (m, 3H), 6.44 (s, 1H),6.40 (s, 1H), 5.21-5.06 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 4.52 (t, J=8.6 Hz, 2H), 2.95 (t, J=8.6Hz, 2H); MS (ES+) m/z 559.1 (M+23).

EXAMPLE 12.24 Synthesis ofN-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-(4-chlorophenyl)ethylamine to replacecyclohexanemethylamine, and2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (78%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.59(br, 1H), 7.44-7.23 (m, 7H), 7.23-6.11 (m, 2H), 7.10-6.94 (m, 2H), 6.73(d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 4.94-4.65 (m, 4H), 4.47(t, J=8.6 Hz, 2H), 3.57-3.42 (m, 2H), 2.95 (t, J=8.3 Hz, 2H), 2.84 (t,J=6.7 Hz, 2H); MS (ES+) m/z 573.1 (M+23).

EXAMPLE 12.25 Synthesis ofN-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-methoxyaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (68%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.56-8.43 (m, 2H), 7.87 (d, J=7.9 Hz, 2H), 7.45 (d, J=7.9 Hz, 2H),7.23-7.15 (m, 2H), 7.11-6.96 (m, 3H), 6.90 (d, J=7.9 Hz, 1H), 6.76 (d,J=7.9 Hz, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 5.01 (ABq, 2H), 4.85 (ABq,2H), 4.53 (t, J=8.6 Hz, 2H), 3.90 (s, 3H), 3.07-2.92 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ178.0, 164.7, 161.9, 161.4, 148.1, 141.8, 139.7, 134.9,132.7, 128.8, 127.8, 127.7, 127.6, 124.1, 124.0, 123.7, 121.2, 120.1,120.0, 119.8, 118.9, 109.9, 109.1, 93.4, 93.3, 80.7, 72.4, 57.8, 55.8,43.9, 29.1; MS (ES+) m/z 519.1 (M+1).

EXAMPLE 12.26 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-(trifluoromethyl)aniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-[2-(trifluoromethyl)phenyl]benzamidewas obtained (53%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.39(d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.62 (dd,J=15.9, 7.9 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.31-7.14 (m, 4H), 7.04(dd, J=7.6, 7.6, 0.7 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H), 6.47 (s, 1H), 6.43(s, 1H), 5.02 (ABq, 2H), 4.85 (ABq, 2H), 4.54 (t, J=8.7 Hz, 2H),3.10-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 164.9, 161.9, 161.3,142.6, 141.7, 140.4, 133.8, 133.1, 132.7, 128.8, 128.0, 127.7, 126.2,124.6, 124.1 (2C), 123.7, 120.0, 118.8, 109.0, 93.3, 80.6, 72.4, 57.7,43.8, 29.0; MS (ES+) m/z 557.1 (M+1).

EXAMPLE 12.27 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-phenylbenzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using aniline to replace cyclohexanemethylamine,and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-phenylbenzamidewas obtained (90%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.34(s, 1H), 7.83 (d, J=7.8 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.39-7.23 (m,4H), 7.23-6.97 (m, 4H), 6.72 (d, J=7.7 Hz, 1H), 6.44 (s, 1H), 6.38 (s,1H), 4.92 (ABq, 2H), 4.77 (ABq, 2H), 4.48 (t, J=8.5 Hz, 2H), 2.89 (t,J=8.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.1, 165.2, 161.8, 161.3,141.6, 139.4, 137.9, 134.6, 132.4, 128.8, 128.7, 127.8, 127.4, 124.4,123.9, 123.7, 120.2, 119.9, 119.7, 118.7, 109.1, 93.2, 80.4, 72.3, 57.7,43.7, 28.8; MS (ES+) m/z 489.1 (M+1).

EXAMPLE 12.28 Synthesis ofN-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using methylamine hydrochloride to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (86%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.71(d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.22-7.12 (m, 2H), 7.02 (t,J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.42 (s, 1H),6.39 (s, 1H), 4.95 (ABq, 2H), 4.81 (ABq, 2H), 4.53-4.34 (m, 2H), 2.95(d, J=4.0 Hz, 3H), 2.90-2.73 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.2,167.5, 161.9, 161.4, 141.8, 139.0, 134.2, 132.5, 128.8, 127.6, 127.4,124.0, 123.7, 120.0, 119.8, 118.7, 109.2, 93.3, 80.6, 72.4, 57.7, 43.8,28.9, 26.8; MS (ES+) m/z 427.1 (M+1).

EXAMPLE 12.29 Synthesis ofN-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-fluoroaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (75%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.42(ddd, J=8.1, 8.1, 1.2 Hz, 1H), 8.16-7.99 (m, 1H), 7.88 (d, J=8.1 Hz,2H), 7.47 (d, J=8.1 Hz, 2H), 7.25-7.01 (m, 6H), 6.77 (d, J=7.7 Hz, 1H),6.49 (s, 1H), 6.43 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.55 (t,J=8.6 Hz, 2H), 3.10-2.91 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 164.8,161.8, 161.3, 152.7 (d, J=243.1 Hz), 141.7, 140.1, 134.0, 132.6, 128.7,127.7 (2C), 126.3 (d, J=9.8 Hz, 2C), 124.7, 124.6 (d, J=3.9 Hz), 124.0,123.6, 121.8, 119.9 (2C), 118.7, 114.8 (d, J=19.2 Hz, 2C), 109.0, 93.2,80.6, 72.3, 57.7, 43.7, 29.0; MS (ES+) m/z 507.1 (M+1).

EXAMPLE 12.30 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-thiopheneethylamine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2-ylethyl)benzamidewas obtained (74%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.71(d, J=7.9 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 7.24-7.13 (m, 3H), 7.04 (dd,J=7.5, 7.5 Hz, 1H), 6.95 (dd, J=5.0, 3.5 Hz, 1H), 6.86 (d, J=3.5 Hz,1H), 6.74 (d, J=7.6 Hz, 1H), 6.51-6.46 (m, 1H), 6.46 (s, 1H), 6.42 (s,1H), 4.97 (ABq, 2H), 4.83 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.78-3.57(m, 2H), 3.13 (t, J=6.2 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); ¹³C NMR (75MHz, CDCl₃) δ 177.9, 166.8, 161.8, 161.3, 141.7, 141.1, 139.2, 134.1,132.5, 128.7, 127.5, 127.4, 127.0, 125.4, 123.9 (2C), 123.6, 119.9 (2C),118.7, 109.0, 93.2, 80.5, 72.3, 57.6, 43.7, 41.2, 29.8, 28.9; MS (ES+)m/z 523.1 (M+1).

EXAMPLE 12.31 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using ammonia in dry dichloromethane to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (81%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.78(d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.20-7.07 (m, 2H), 6.99 (t,J=7.4 Hz, 1H), 6.85 (s, 1H), 6.71 (d, J=7.6 Hz, 1H), 6.41 (br s, 1H),6.35 (br s, 1H), 6.20 (s, 1H), 4.94 (ABq, 2H), 4.78 (ABq, 2H), 4.46 (t,J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.6,168.7, 161.5, 160.9, 141.4, 139.3, 132.7, 132.1, 128.4, 127.8, 127.0,123.6, 123.3, 119.6, 118.4, 108.8, 92.8, 80.2, 72.0, 57.3, 43.4, 28.6;MS (ES+) m/z 413.1 (M+1).

EXAMPLE 12.32 Synthesis ofN-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 5-aminoindan to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (65%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.83(d, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=8.1 Hz, 2H),7.28-7.21 (m, 2H), 7.21-7.14 (m, 2H), 7.08-6.97 (m, 1H), 6.74 (d, J=7.7Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.99 (ABq, 2H), 4.83 (ABq, 2H),4.53 (t, J=8.6 Hz, 2H), 3.03-2.80 (m, 6H), 2.15-1.97 (m, 2H); MS (ES+)m/z 529.1 (M+1).

EXAMPLE 12.33 Synthesis of1′-[4(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using morpholine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,1′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (58%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.44-7.35 (m, 4H), 7.24-7.15 (m, 2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H),6.76 (d, J=7.5 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98 (ABq, 2H), 4.85(ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.87-3.40 (m, 8H), 3.08-2.93 (m, 2H);MS (ES+) m/z 483.1 (M+1).

EXAMPLE 12.34 Synthesis ofN-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-ethylaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (49%) as a colorless solid: mp 203-204° C.; ¹H NMR (300MHz, CDCl₃) δ7.96-7.83 (m, 3H), 7.69 (s, 1H), 7.52-7.44 (m, 2H),7.31-7.13 (m, 5H), 7.10-7.02 (m, 1H), 6.82-6.74 (m, 1H), 6.49 (s, 1H),6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.51 (m, 2H),3.11-2.92 (m, 2H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 178.0, 165.2, 161.9, 161.3, 141.8, 139.8, 135.1,134.9, 134.6, 132.7, 128.8, 128.6, 127.8, 127.7, 126.8, 125.8, 124.1,123.7, 120.0, 119.9, 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0,24.4, 14.0; MS (ES+) m/z 517.2 (M+1).

EXAMPLE 12.35 Synthesis ofN-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2,6-dimethylaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (28%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,CDCl₃) δ7.95-7.89 (m, 2H), 7.51-7.45 (m, 2H), 7.37 (s, 1H), 7.24-7.02(m, 6H), 6.82-6.75 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H),4.86 (ABq, 2H), 4.60-4.50 (m, 2H), 3.12-2.91 (m, 2H), 2.27 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ178.0, 165.3, 161.9, 161.4, 141.8, 139.8, 135.5,134.1, 133.6, 132.7, 128.8, 128.3, 127.9, 127.8, 127.6, 124.0, 123.7,120.0, 118.8, 109.1, 93.3, 80.7, 72.4, 57.8, 43.8, 29.0, 18.5; MS (ES+)m/z 517.2 (M+1).

EXAMPLE 12.36 Synthesis ofN-(3-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 3-fluoroaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (50%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,CDCl₃) δ8.03 (s, 1H), 7.89-7.82 (m, 2H), 7.63-7.56 (m, 1H), 7.48-7.41(m, 2H), 7.34-7.15 (m, 4H), 7.09-7.01 (m, 1H), 6.89-6.80 (m, 1H),6.78-6.72 (m, 1H), 6.47 (s, 1H), 6.42 (s, 1H), 5.01 (ABq, 2H), 4.82(ABq, 2H), 4.57-4.48 (m, 2H), 3.01-2.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ178.3, 163.6 (d, J_(C-F)=248.0 Hz), 161.4, 141.7, 139.7, 139.5 (d,J_(C-F)=10.8 Hz), 134.3, 132.4, 130.0 (d, J_(C-F)=9.4 Hz), 128.8, 127.9,127.6, 124.1, 123.8, 120.0, 119.7, 118.7, 115.4 (d, J_(C-F)=2.9 Hz),111.2 (d, J_(C-F)=21.3 Hz), 109.2, 107.6 (d, J_(C-F)=26.4 Hz), 93.3,80.5, 72.4, 57.8, 43.8, 28.9; MS (ES+) m/z 507.2 (M+1).

EXAMPLE 12.37 Synthesis ofN-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2,4-dimethylaniline to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (59%) as a colorless solid: mp 249-251° C.; ¹H NMR (300MHz, CDCl₃) δ7.91-7.83 (m, 2H), 7.76-7.69 (m, 1H), 7.56 (s, 1H),7.50-7.43 (m, 2H), 7.28-7.17 (m, 2H), 7.09-7.01 (m, 3H), 6.80-6.74 (m,1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H),4.60-4.51 (m, 2H), 3.11-2.92 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 178.0, 165.2, 161.9, 161.3, 141.7, 139.6, 135.3,134.6, 132.9, 132.6, 131.2, 129.8, 128.7, 127.7, 127.4, 124.0, 123.6(2C), 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 57.7, 43.8, 29.0,20.9, 17.8; MS (ES+) m/z 517.2 (M+1).

EXAMPLE 12.38 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-thiophenemethylamine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-(thiophen-2-ylmethyl)benzamidewas obtained (48%) as a colorless solid: mp 167-168° C.; ¹H NMR (300MHz, CDCl₃) δ7.81-7.73 (m, 2H), 7.43-7.37 (m, 2H), 7.27-7.16 (m, 3H),7.07-7.00 (m, 2H), 6.99-6.95 (m, 1H), 6.75-6.70 (m, 1H), 6.48-6.40 (m,3H), 4.99 (ABq, 2H), 4.84 (ABq, 2H), 4.83-4.78 (m, 2H), 4.59-4.50 (m,2H), 3.09-2.90 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 166.5, 161.9,161.3, 141.7, 140.6, 139.4, 133.7, 132.6, 128.7, 127.7, 127.5, 126.9,126.2, 125.3, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4,57.7, 43.8, 38.8, 29.0; MS (ES+) m/z 509.2 (M+1).

EXAMPLE 12.39 Synthesis ofN-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using ethylamine (2 M solution intetrahydrofuran) to replace cyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (57%) as a colorless solid: mp190-191° C.; ¹H NMR (300 MHz, CDCl₃) δ7.79-7.71 (m, 2H), 7.44-7.36 (m,2H), 7.24-7.15 (m, 2H), 7.08-6.99 (m, 1H), 6.77-6.70 (m, 1H), 6.47 (s,1H), 6.43 (s, 1H), 6.14-6.04 (m, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H),4.59-4.50 (m, 2H), 3.54-3.43 (m, 2H), 3.09-2.90 (m, 2H), 1.28-1.21 (m,3H); ¹³C NMR (75 MHz, CDCl₃) δ178.0, 166.8, 161.9, 161.3, 141.8, 139.1,134.4, 132.6, 128.7, 127.5 (2C), 124.0, 123.6, 120.0, 118.8, 109.1,93.3, 80.6, 72.4, 57.7, 43.8, 34.9, 29.0, 14.8; MS (ES+) m/z 441.2(M+1).

EXAMPLE 12.40 Synthesis ofN-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-methoxyethylamine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (49%) as a colorless solid: mp 182-183° C.; ¹H NMR (300MHz, CDCl₃) δ7.81-7.73 (m, 2H), 7.44-7.37 (m, 2H), 7.23-7.15 (m, 2H),7.07-7.00 (m, 1H), 6.77-6.70 (m, 1H), 6.56-6.41 (m, 3H), 5.00 (ABq, 2H),4.85 (ABq, 2H), 4.60-4.51 (m, 2H), 3.68-3.60 (m, 2H), 3.59-3.52 (m, 2H),3.38 (s, 3H), 3.08-2.94 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.9, 166.9,161.9, 161.3, 141.8, 139.3, 134.1, 132.6, 128.7, 127.6, 127.5, 124.0,123.6, 120.0 (2C), 118.8, 109.1, 93.3, 80.6, 72.4, 71.1, 58.8, 57.7,43.8, 39.7, 29.0; MS (ES+) m/z 471.1 (M+1).

EXAMPLE 12.41 Synthesis ofN-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-ethoxyethylamine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (48%) as a colorless solid: mp 84-85° C.; ¹H NMR (300 MHz,CDCl₃) δ7.80-7.73 (m, 2H), 7.44-7.38 (m, 2H), 7.23-7.15 (m, 2H),7.07-7.00 (m, 1H), 6.77-6.71 (m, 1H), 6.58-6.50 (m, 1H), 6.47 (s, 1H),6.43 (s, 1H), 5.00 (ABq, 2H), 4.85 (ABq, 2H), 4.60-4.50 (m, 2H),3.68-3.48 (m, 6H), 3.11-2.91 (m, 2H), 1.21 (t, J=7.0, Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ177.9, 166.9, 161.8, 161.3, 141.8, 139.2, 134.2, 132.6,128.7, 127.6, 127.5, 124.0, 123.6, 120.0 (2C), 118.8, 109.1, 93.2, 80.6,72.4, 68.9, 66.5, 57.7, 43.8, 39.8, 29.0, 15.1; MS (ES+) m/z 485.1(M+1).

EXAMPLE 12.42 Synthesis ofN-cyclobutyl-4-[(2-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1(2H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using cyclobutylamine hydrochloride to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-cyclobutyl-4-[(2-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1(2H)-yl)methyl]benzamidewas obtained (25%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,CDCl₃) δ8.61-8.55 (m, 1H), 7.85-7.78 (m, 2H), 7.46-7.38 (m, 2H),7.29-7.15 (m, 2H), 7.07-6.93 (m, 2H), 6.46 (s, 1H), 6.44 (s, 1H),5.08-4.90 (m, 2H), 4.80 (ABq, 2H), 4.55-4.46 (m, 2H), 4.46-4.31 (m, 1H),3.05-2.91 (m, 2H), 2.26-2.12 (m, 2H), 2.12-1.95 (m, 2H), 1.72-1.60 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ177.1, 164.9, 161.1, 160.7, 142.0, 139.2,133.7, 132.0, 128.6, 127.7, 126.9, 123.7, 123.1, 120.3, 119.9, 118.8,109.3, 92.4, 79.8, 72.0, 56.9, 44.4, 42.8, 30.0, 28.3, 14.6; MS (ES+)m/z 467.1 (M+1).

EXAMPLE 12.43 Synthesis of4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-aminothiazole to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamidewas obtained (46%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,CDCl₃) δ12.63 (s, 1H), 8.11-8.05 (m, 2H), 7.57-7.47 (m, 3H), 7.31-7.18(m, 3H), 7.08-6.98 (m, 2H), 6.49 (s, 1H), 6.44 (s, 1H), 5.12-4.96 (m,2H), 4.82 (ABq, 2H), 4.58-4.43 (m, 2H), 3.08-2.89 (m, 2H); MS (ES+) m/z496.1 (M+1).

EXAMPLE 12.44 Synthesis ofN-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 3-fluoro-2-methylaniline to replacecyclohexanemethylamine, and4[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (35%) as a colorless solid: mp 143-144° C.; ¹H NMR (300MHz, CDCl₃) δ 7.91-7.84 (m, 2H), 7.74-7.64 (m, 2H), 7.52-7.45 (m, 2H),7.29-7.17 (m, 3H), 7.10-7.02 (m, 1H), 6.96-6.87 (m, 1H), 6.80-6.74 (m,1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H), 4.85 (ABq, 2H),4.60-4.51 (m, 2H), 3.10-2.91 (m, 2H), 2.23 (d, J=1.51 Hz, 3H); MS (ES+)m/z 521.0 (M+1).

EXAMPLE 12.45 Synthesis ofN-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide

Following the procedure as described in EXAMPLE 12 and makingnon-critical variations using 2-ethyl-n-butylamine to replacecyclohexanemethylamine, and4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid to replace3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoicacid,N-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamidewas obtained (60%) as a colorless solid: mp 211-213° C.; ¹H NMR (300MHz, CDCl₃) δ7.78-7.70 (m, 2H), 7.44-7.37 (m, 2H), 7.24-7.15 (m, 2H),7.08-7.00 (m, 1H), 6.77-6.71 (m, 1H), 6.47 (s, 1H), 6.44 (s, 1H),6.08-5.99 (m, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H), 4.59-4.50 (m, 2H),3.44-3.36 (m, 2H), 3.10-2.91 (m, 2H), 1.55-1.30 (m, 5H), 0.97-0.87 (m,6H); MS (ES+) m/z 497.0 (M+1).

EXAMPLE 12.46 Synthesis of2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

To a stirred solution of(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid (0.25 g, 0.74 mmol), triethylamine (0.5 mL), ammonia in dioxane(0.5M, 4.5 mL, 2.3 mmol) in acetonitrile (10 mL) was added2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (0.33 g, 0.9 mmol). The solution was stirred atambient temperature for 18 h then concentrated in vacuo to dryness. Theresidue was dissolved in ethyl acetate (50 mL) and washed with 2 Msodium carbonate (2×25 mL) and 1 M hydrochloric acid (2×25 mL). Theethyl acetate layer was dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo to dryness. Recrystallization from diethylether (25 mL) in a Branson ultrasonic bench top water bath afforded2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide(0.06 g, 23%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.66 (s,1H), 7.29-7.21 (m, 2H), 7.10 (d, J=6.5 Hz, 1H), 7.03-6.90 (m, 2H), 6.55(s, 1H), 6.36 (s, 1H), 4.72 (ABq, 2H), 4.53-4.38 (m, 1H), 4.29 (ABq,2H), 2.92 (t, J=8.6 Hz, 2H); MS (ES+) m/z 337.1 (M+1), 359.1 (M+23).

EXAMPLE 12.47 Synthesis ofN-(4-ethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.46 and makingnon-critical variations using 4-ethylaniline to replace ammonia indioxane,N-(4-ethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (69%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ10.25 (s, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.26 (dd, J=7.3, 7.3 Hz, 1H),7.16-7.09 (m, 3H), 7.08-6.95 (m, 2H), 6.56 (s, 1H), 6.38 (s, 1H), 4.73(ABq, 2H), 4.56 (ABq, 2H), 4.50-4.41 (m, 2H), 2.94 (t, J=8.6 Hz, 2H),2.53 (q, J=7.5 Hz, 2H), 1.11 (t, J=7.6 Hz, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ177.7, 165.3, 161.6, 161.0, 143.2, 139.4, 136.8, 132.6, 129.1,128.5, 123.9, 123.4, 121.2, 120.3, 119.7, 109.5, 92.9, 80.2, 72.6, 57.3,43.5, 28.8, 28.0, 16.2; MS (ES+) m/z 441.1 (M+1).

EXAMPLE 12.48 Synthesis ofN,N-diethyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.46 and makingnon-critical variations using diethylamine to replace ammonia indioxane,N,N-diethyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (54%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.28-7.21 (m, 1H), 7.10 (d, J=7.3 Hz, 1H), 6.98 (dd, J=7.5, 7.5 Hz,1H), 6.91 (d, J=7.8 Hz, 1H), 6.57 (s, 1H), 6.37 (s, 1H), 4.76-4.66 (m,2H), 4.60 (ABq, 2H), 4.50-4.41 (m, 2H), 3.46-3.36 (m, 2H), 3.31-3.20 (m,2H), 2.93 (t, J=8.6 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H), 1.00 (t, J=7.1 Hz,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.8, 165.0, 161.5, 160.9, 143.4,132.7, 129.0, 123.8, 123.2, 121.3, 120.2, 119.9, 109.6, 92.8, 80.2,72.5, 57.3, 41.7, 41.0, 28.8, 14.6, 13.5; MS (ES+) m/z 393.1 (M+1).

EXAMPLE 12.49 Synthesis ofN-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

To a stirred solution of(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid (0.25 g, 0.74 mmol), isobutylchloroformate (0.11 mL, 0.81 mmol),N-methylmorpholine (0.09 mL, 0.81 mmol) in dichloromethane (10 mL) wasadded 3,3-dimethylbutylamine (0.11 g, 1.1 mmol). The solution wasstirred at ambient temperature for 16 h, diluted with dichloromethane(10 mL) and washed with 2 M sodium carbonate (2×25 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to dryness. The residue was purified by flash chromatography withethyl acetate in hexanes (30% to 50% gradient) to affordN-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide(0.13 g, 41%) as a colorless solid: mp 161-163° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.14 (dd, J=5.4, 5.4 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H),7.11 (d, J=6.9 Hz, 1H), 7.03-6.95 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53(s, 1H), 6.37 (s, 1H), 4.71 (ABq, 2H), 4.51-4.40 (m, 2H), 4.38-4.20 (m,2H), 3.12-3.01 (m, 2H), 2.93 (t, J=8.6 Hz, 2H), 1.37-1.27 (m, 2H), 0.85(s, 9H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.6, 166.3, 161.5, 160.9, 143.1,132.7, 129.0, 123.8, 123.3, 121.3, 120.2, 119.8, 109.4, 92.8, 80.2,72.5, 57.3, 43.2, 43.0, 35.9, 30.0, 29.7, 28.8; MS (ES+) m/z 421.2(M+1).

EXAMPLE 12.50 Synthesis ofN-[3-(1-methylethoxy)propyl]-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 3-isopropoxypropylamine to replace3,3-dimethylbutylamine,N-[3-(1-methylethoxy)propyl]-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (22%) as a colorless solid: mp 149-151° C.; ¹H NMR (300MHz, DMSO-d₆) δ8.18 (dd, J=5.4, 5.4 Hz, 1H), 7.25 (dd, J=7.7, 7.7 Hz,1H), 7.11 (d, J=6.9 Hz, 1H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.71 (dd, J=21.2, 9.3 Hz,1H), 4.50-4.41 (m, 1H), 4.31 (ABq, 1H), 3.52-3.39 (m, 1H), 3.36-3.30 (m,1H), 3.11 (dd, J=12.8, 6.7 Hz, 1H), 2.93 (t, J=8.5 Hz, 1H), 1.65-1.52(m, 1H), 1.02 (d, J=6.1 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.6,166.5, 161.5, 160.9, 143.1, 132.1, 132.7, 129.0, 123.8, 123.3, 121.3,120.2, 119.8, 109.4, 92.8, 80.2, 72.5, 71.0, 65.2, 57.3, 43.0, 36.6,30.2, 28.8, 22.5; MS (ES+) m/z 437.2 (M+1).

EXAMPLE 12.51 Synthesis of2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-propylacetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using propylamine to replace3,3-dimethylbutylamine,2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-propylacetamidewas obtained (44%) as a colorless solid: mp 207-209° C.; ¹H NMR (300MHz, DMSO-d₆) δ 8.19 (dd, J=5.5, 5.5 Hz, 1H), 7.25 (dd, J=7.7, 7.7 Hz,1H), 7.11 (d, J=6.7 Hz, 1H), 6.99 (dd, J=7.2, 7.2 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.72 (ABq, 2H), 4.50-4.41 (m,2H), 4.32 (ABq, 2H), 3.03 (dd, J=12.9, 6.7 Hz, 2H), 2.93 (t, J=8.6 Hz,2H), 1.49-1.30 (m, 2H), 0.82 (t, J=7.39 Hz, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ177.6, 166.4, 161.5, 160.9, 143.2, 132.7, 129.0, 123.8, 123.3,121.3, 120.2, 119.8, 109.4, 92.8, 80.2, 72.5, 57.3, 43.0, 41.0, 28.8,22.8, 11.8; MS (ES+) m/z 379.1 (M+1).

EXAMPLE 12.52 Synthesis ofN-methyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-phenylacetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using N-methylaniline to replace3,3-dimethylbutylamine,N-methyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)-N-phenylacetamidewas obtained (27%) as a colorless solid: mp 234-238° C.; ¹H NMR (300MHz, DMSO-d₆) δ7.62-7.35 (m, 5H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.09 (d,J=6.7 Hz, 1H), 7.02-6.93 (m, 1H), 6.54 (s, 1H), 6.36 (s, 1H), 4.73-4.61(m, 2H), 4.50-4.40 (m, 2H), 4.19 (ABq, 2H), 3.18 (br s, 3H), 2.92 (dd,J=8.5, 8.5 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.5, 165.9, 161.5,160.9, 143.1, 132.6, 130.5, 128.9, 127.9, 123.8, 123.3, 121.3, 120.2,119.8, 109.7, 92.8, 80.0, 72.5, 57.2, 42.4, 37.7, 28.8; MS (ES+) m/z427.1 (M+1).

EXAMPLE 12.53 Synthesis ofN-(2,5-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 2,5-dimethylaniline to replace3,3-dimethylbutylamine,N-(2,5-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (63%) as a colorless solid: mp 250-252° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.63 (s, 1H), 7.33-7.25 (m, 1H), 7.21-6.97 (m, 6H),6.91-6.85 (m, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 4.74 (dd, J=23.9, 9.4 Hz,2H), 4.60 (dd, J=29.3, 17.3 Hz, 2H), 4.49-4.41 (m, 2H), 2.92 (dd, J=8.6,8.6 Hz, 2H), 2.20 (s, 3H), 2.14 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆)δ177.7, 165.7, 161.6, 160.9, 143.1, 136.0, 135.5, 132.8, 130.7, 129.1,126.6, 125.9, 123.9, 123.4, 121.3, 120.2, 119.7, 109.4, 92.8, 80.2,72.5, 57.3, 43.3, 28.8, 21.0, 17.9; MS (ES+) m/z 441.2 (M+1).

EXAMPLE 12.54 Synthesis ofN-(2,4-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 2,4-dimethylaniline to replace3,3-dimethylbutylamine,N-(2,4-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (67%) as a colorless solid: mp 277-279° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.62 (s, 1H), 7.28 (dd, J=7.6, 7.6 Hz, 1H), 7.21 (d,J=8.0 Hz, H), 7.12 (d, J=6.9 Hz, 1H), 7.08-6.89 (m, 4H), 6.53 (s, 1H),6.38 (s, 1H), 4.74 (ABq, 2H), 4.59 (m, 2H), 4.49-4.41 (m, 2H), 2.91 (dd,J=8.6, 8.6 Hz, 2H), 2.21 (s, 3H), 2.15 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ177.7, 165.7, 161.6, 160.9, 143.1, 135.1, 133.6, 132.8, 132.3,131.4, 129.0, 128.6, 127.0, 125.5, 123.9, 121.3, 120.2, 119.7, 109.4,92.8, 80.2, 72.5, 57.4, 55.4, 43.3, 28.8, 20.9, 18.3; MS (ES+) m/z 441.2(M+1).

EXAMPLE 12.55 Synthesis ofN-(2,3-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 2,3-dimethylaniline to replace3,3-dimethylbutylamine,N-(2,3-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (55%) as a colorless solid: mp 251-253° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.76 (s, 1H), 7.29 (dd, J=7.4, 7.4 Hz, 1H), 7.15-6.96 (m,6H), 6.52 (s, 1H), 6.37 (s, 1H), 4.74 (ABq, 2H), 4.60 (ABq, 2H),4.49-4.40 (m, 2H), 2.91 (dd, J=8.6, 8.6 Hz, 2H), 2.21 (s, 3H), 2.06 (s,3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.7, 165.8, 161.8, 160.9, 143.1,137.6, 136.0, 132.8, 131.8, 129.0, 127.7, 125.7, 124.0, 123.4, 121.3,120.2, 119.7, 109.4, 92.8, 80.2, 72.5, 57.3, 43.3, 28.8, 20.6, 14.5; MS(ES+) m/z 441.2 (M+1).

EXAMPLE 12.56 Synthesis ofN-(2,6-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 2,6-dimethylaniline to replace3,3-dimethylbutylamine,N-(2,6-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamidewas obtained (67%) as a colorless solid: mp 261-262° C.; ¹H NMR (300MHz, DMSO-d₆) δ9.66 (s, 1H), 7.30 (dd, J=7.7, 7.7 Hz, 1H), 7.16-6.98 (m,6H), 6.51 (s, 1H), 6.37 (s, 1H), 4.75 (ABq, 2H), 4.67-4.52 (m, 2H),4.49-4.40 (m, 2H), 2.90 (dd, J=8.6, 8.6 Hz, 2H), 2.12 (s, 6H); ¹³C NMR(75 MHz, DMSO-d₆) δ177.7, 165.4, 161.5, 160.9, 143.0, 135.7, 135.0,132.9, 128.9, 128.2, 127.1, 123.9, 123.4, 121.3, 120.2, 119.7, 109.3,92.8, 80.2, 72.5, 57.4, 43.0, 28.8, 18.6, 15.6; MS (ES+) m/z 441.2(M+1).

EXAMPLE 12.57 Synthesis ofN-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using methylamine hydrochloride to replace3,3-dimethylbutylamine,5-[(2-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylicacid to replace(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid,N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamidewas obtained (96%) as a colorless solid: mp 202-203° C. (diethylether/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.31-7.27 (m, 2H), 7.19-7.17 (m, 1H), 7.10-7.05 (m, 1H), 6.95-6.92 (m,1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.09 (s, 1H), 5.94 (br s, 1H),5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H), 2.92 (d, J=3.0Hz, 3H); MS (ES+) m/z 487.3 (M+1).

EXAMPLE 12.58 Synthesis of5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using 7 N ammonia solution in methanol toreplace 3,3-dimethylbutylamine, and5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylicacid to replace(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid,5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamidewas obtained (86%) as a colorless solid: mp 172-174° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.32-7.27 (m, 1H), 7.20-7.17 (m, 1H), 7.11-7.06 (m, 1H), 6.97-6.94 (m,1H), 6.70 (s, 1H), 6.49 (s, 1H), 6.09-6.02 (m, 3H), 5.83 (ABq, 2H),5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H); MS (ES+) m/z473.2 (M+1).

EXAMPLE 12.59 Synthesis ofN,N-dimethyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide

Following the procedure as described in EXAMPLE 12.49 and makingnon-critical variations using dimethylamine hydrochloride to replace3,3-dimethylbutylamine, and5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylicacid to replace(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)aceticacid,N,N-dimethyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamidewas obtained (32%) as a colorless solid: mp 96-98° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.32-7.27 (m, 1H), 7.19-7.17(m, 1H), 7.10-7.05 (m, 1H), 6.96-6.94 (m, 1H), 6.50 (s, 1H), 6.40 (s,1H), 6.09 (s, 1H), 5.86-5.85 (m, 2H), 5.05-4.87 (m, 3H), 4.68-4.65 (m,1H); MS (ES+) m/z 501.3 (M+1).

EXAMPLE 12.60 Synthesis of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a solution of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (0.43 g, 1.00 mmol) in dichloromethane was added oxalyl chloride(0.2 mL, 2.4 mmol) followed by N,N-dimethylformamide (1 drop). Thereaction mixture was stirred at ambient temperature for 5 h andconcentrated in vacuo. The residue was dissolved in dichloromethane (10mL) and added to a 0.5 M solution of ammonia in 1,4-dioxane (5 mL). Thereaction mixture was stirred at ambient temperature for 18 h andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with ethyl acetate to afford4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.15 g, 35%): m.p. 236-238° C. (ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆) δ 7.93-7.80 (m, 3H), 7.39-7.33 (m, 3H), 7.25-7.14 (m, 2H),7.02-6.94 (m, 2H), 6.50 (s, 1H), 6.08 (s, 1H), 4.94 (ABq, 2H), 4.72(ABq, 2H), 4.16-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.2, 167.9,155.2, 144.6, 142.5, 140.0, 138.3, 134.0, 132.1, 129.2, 128.3, 127.4,124.1, 123.6, 121.6, 111.4, 109.8, 99.3, 79.9, 64.6, 64.0, 57.2, 43.2;MS (ES+) m/z 429.0 (M+1).

EXAMPLE 12.61 Synthesis of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a solution of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (1.04 g, 2.42 mmol) in anhydrous chloroform (50 mL) was addedoxalyl chloride (0.50 mL, 5.7 mmol) and anhydrous N,N-dimethylformamide(2 drops). The reaction mixture was stirred at ambient temperature for 2h and concentrated in vacuo. The residue was dissolved in anhydroustetrahydrofuran (36 mL), cooled to 0° C. and 7 M methanolic ammonia(5.20 mL, 36.3 mmol) was added. The reaction mixture was stirred at 0°C. for 1 h and at ambient temperature for 2 h, filtered and concentratedin vacuo. The residue was purified by column chromatography and elutedwith acetone/dichloromethane (1/9), followed by recrystallization fromdichloromethane/diethyl ether to afford3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide(1.03 g, 99%) as a colorless solid: mp 130-135° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.81 (s, 1H),7.71-7.69 (m, 1H), 7.48-7.39 (m, 2H), 7.21-7.15 (m, 2H), 7.04-6.99 (m,1H), 6.76-6.74 (m, 1H), 6.49 (s, 1H), 6.23 (s, 1H), 6.10 (br s, 1H),5.71 (br s, 1H), 5.14-5.09 (m, 1H), 4.95-4.81 (m, 2H), 4.67-4.64 (m,1H), 4.19-4.08 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7, 168.7, 155.3,144.7, 141.8, 138.4, 136.5, 134.0, 132.1, 130.8, 129.4, 128.9, 126.8,126.5, 124.0, 123.7, 120.9, 111.4, 109.2, 99.5, 80.0, 64.5, 63.9, 58.1,43.8; MS (ES+) m/z 428.8 (M+1).

EXAMPLE 12.62 Synthesis ofN,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a solution of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (0.50 g, 1.16 mmol) in anhydrous chloroform (25 mL) was addedoxalyl chloride (0.25 mL, 2.9 mmol) and anhydrous N,N-dimethylformamide(1 drop). The reaction mixture was stirred at ambient temperature for 2h and concentrated in vacuo. The residue was dissolved in anhydrousdichloromethane (10 mL) and the resultant solution was added dropwise toa cooled (0° C.) solution of dimethylamine hydrochloride (1.56 g, 18.9mmol) and triethylamine (5.27 mL, 37.8 mmol) in anhydrousdichloromethane (10 mL). The reaction mixture was stirred at 0° C. for45 min and at ambient temperature for 3 h, filtered and concentrated invacuo. The residue was recrystallized from hexanes to affordN,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.04 g, 8%) as a light brown solid: mp: 90-96° C. (hexanes); ¹H NMR(300 MHz, CDCl₃) δ 7.37-7.34 (m, 4H), 7.21-7.14 (m, 2H), 7.04-7.00 (m,1H), 6.77-6.75 (m, 1H), 6.49 (s, 1H), 6.19 (s, 1H), 5.08-5.03 (m, 1H),4.93-4.82 (m, 2H), 4.67-4.64 (m, 1H), 4.20-4.09 (m, 4H), 3.08 (s, 3H),2.90 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 171.1, 155.3, 144.7,141.9, 138.3, 137.0, 136.0, 132.1, 129.1, 128.9, 128.3, 126.6, 126.0,124.0, 123.6, 120.9, 111.5, 109.2, 99.5, 80.2, 64.5, 63.9, 58.0, 43.9,39.6, 35.3; MS (ES+) m/z 456.8 (M+1).

EXAMPLE 12.63 Synthesis ofN-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide

A 50 mL round-bottom flask was charged with2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid (0.43 g, 1.0 mmol), methylamine hydrochloride (0.14 g, 2.0 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.4mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), N-methylmorpholine(0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL). The reactionmixture was stirred under nitrogen at ambient temperature for 20 h, andpoured into water (200 mL). The solid was collected by filtration,washed with water, dried and purified by column chromatography andeluted with a 0% to 50% gradient of ethyl acetate in dichloromethane toaffordN-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide (0.41 g, 92%) as an off-whitesolid: ¹H NMR (300 MHz, CDCl₃)

8.43 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz,1H), 7.20-7.07 (m, 2H), 6.95 (t, J=7.5, 1H), 6.81 (d, J=7.8 Hz, 1H),6.46 (d, J=1.2 Hz, 1H), 6.43 (d, J=1.2 Hz, 1H), 5.16 (ABq, 2H), 4.70(ABq, 2H), 4.20-4.05 (m, 4H), 2.77 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.3, 167.6, 154.9, 152.7, 150.1, 144.5, 143.3, 138.1, 136.2, 132.5,131.6, 129.0, 123.7, 123.1, 122.9, 122.2, 112.4, 109.6, 99.0, 79.7,64.6, 64.1, 57.7, 43.3, 26.5; MS (ES+) m/z 443.9 (M+1).

EXAMPLE 12.64 Synthesis ofN-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamidedihydrochloride

A 50 mL round-bottom flask was charged with2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid (0.43 g, 1.0 mmol), tert-butyl 2-aminomethylcarbamate (0.32 g, 2.0mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride(0.26 g, 1.35 mmol), 1-hydroxybenzotriazole (0.20 g, 1.5 mmol),N-methylmorpholine (0.4 mL, 3.6 mmol) and N,N-dimethylformamide (7 mL).The reaction mixture was stirred under nitrogen at ambient temperaturefor 20 h and poured into water (200 mL). The solid was collected byfiltration, washed with water, dried and dissolved in tetrahydrofuran(20 mL). A 4 M solution of hydrochloric acid in dioxane was added andthe reaction mixture was stirred for 16 h, diluted with diethyl ether(50 mL) and filtered to affordN-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamidedihydrochloride (0.31 g, 57%) as an off-white solid: ¹H NMR (300 MHz,CDCl₃) δ 10.01 (s, 2H), 9.02 (t, J=5.4 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz,1H), 8.20 (s, 2H), 8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.41 (dd, J=7.8, 4.9Hz, 1H), 7.20-7.08 (m, 2H), 6.99-6.86 (m, 2H), 6.46 (s, 1H), 6.43 (s,1H), 5.26 (ABq, 2H), 4.71 (ABq, 2H), 4.19-4.05 (m, 4H), 3.58-3.47 (m,2H), 3.06-2.93 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 167.6, 154.9,152.9, 150.0, 144.5, 143.3, 138.1, 137.1, 132.5, 130.9, 129.0, 123.8,123.1, 122.9, 122.2, 112.3, 109.7, 99.0, 79.7, 64.6, 64.1, 57.7, 43.2,38.8, 37.6; MS (ES+) m/z 472.9 (M+1).

EXAMPLE 12.65 Synthesis ofN-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide

To a stirred solution of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was addedthionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at refluxfor 2 h and concentrated in vacuo to afford4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoylchloride (0.45 g) as a pale yellow solid. To a solution of2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol)in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoylchloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambienttemperature for 42 h and was washed with 10% w/v hydrochloric acid (10mL), water (10 mL) and brine (10 mL). The organic phase was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography and eluted withhexanes/ethyl acetate (1/1) to affordN-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.262 g, 49%) as a colorless solid: mp 245-251° C.; ¹H NMR (300 MHz,CDCl₃) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H),7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52(s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H),4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); ¹³CNMR (75 MHz, CDCl₃) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7,141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d,J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z523.0 (M+1).

EXAMPLE 13 Synthesis of5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid

A solution of methyl5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate(5.5 g, 13.0 mmol) and sodium hydroxide (1.04 g, 26.0 mmol) in water 100ml) and methanol (40 mL) was stirred at 65° C. for 16 h. The solventmethanol was evaporated under reduced pressure, and the residue wascooled in ice-bath and acidified with 10% hydrochloric acid to pH 1-2.The solid precipitate was filtered off, and recrystallized from ethanol(100 mL) to afford5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid (5.10 g, 92%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.36-6.92 (m, 5H), 6.51 (s, 1H), 6.44 (d, J=3.5 Hz, 1H), 6.40 (s, 1H),5.02 (ABq, 2H), 4.81 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.04-2.91 (m,2H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 161.6, 160.9, 159.6, 153.7, 145.0,142.1, 132.7, 129.1, 124.0, 123.7, 121.0, 120.4, 119.6, 119.1, 111.1,109.7, 92.9, 80.0, 72.6, 57.4, 37.3, 28.8; MS (ES+) m/z 403.8 (M+1).

EXAMPLE 13.1 Synthesis ofN,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide

A mixture of5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid (4.85 g, 12 mmol), thionyl chloride (11.90 g, 100 mmol) and a fewdrops of N,N-dimethylformamide in chloroform (60 mL) was stirred atambient temperature for 16 h. The solvent and excess of thionyl chloridewere evaporated under reduced pressure. The residue was dissolved indichloromethane (50 mL). To the above solution (5 mL, 1.2 mmol) wasadded dimethylamine hydrochloride (0.81 g, 10 mmol), and triethylamine(1.01 g, 10 mmol). The mixture was stirred at ambient temperature for 3h. The reaction mixture was diluted with dichloromethane (100 mL) andextracted with water (2×100 mL), dried over magnesium sulfate andfiltered. The filtrate was evaporated under reduced pressure, and theresidue was purified by column chromatography withdichloromethanemethanol (100:1-20:1) to affordN,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide(0.22 g, 42%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.31-6.90(m, 5H), 6.43-6.37 (m, 3H), 4.97 (ABq, 2H), 4.78 (ABq, 2H), 4.52 (t,J=8.6 Hz, 2H), 3.11 (s, 6H), 2.96 (t, J=8.6 Hz, 2H); ¹³C NMR (75 MHz,CDCl₃) δ177.2, 161.6, 161.0, 159.4, 151.3, 147.5, 142.2, 132.6, 129.1,124.1, 123.7, 121.0, 120.4, 119.5, 116.8, 110.4, 109.8, 92.9, 80.1,72.6, 57.4, 37.1, 28.8; MS (ES+) m/z 431.1 (M+1).

EXAMPLE 13.2 Synthesis ofN-methyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide

Following the procedure as described in EXAMPLE 13.1 and makingnon-critical variations using methylamine hydrochloride to replacedimethylamine hydrochloride,N-methyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamidewas obtained (37%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.29-6.89 (m, 5H), 6.66 (s, 1H), 6.42-6.35 (m, 3H), 4.91 (ABq, 2H),4.78 (ABq, 2H), 4.53 (t, J=8.5 Hz, 2H) 2.98-2.87 (m, 5H); ¹³C NMR (75MHz, CDCl₃) δ177.8, 161.9, 161.3, 158.7, 150.5, 148.0, 141.3, 132.5,128.9, 124.1, 123.9, 120.0, 119.9, 118.8, 114.8, 111.1, 108.8, 93.3,80.4, 72.4, 57.7, 37.2, 29.0, 25.8; MS (ES+) m/z 417.2 (M+1).

EXAMPLE 13.3 Synthesis of2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide

Following the procedure as described in EXAMPLE 13.1 and makingnon-critical variations using 4 M ammonia solution in dioxane to replacedimethylamine hydrochloride,2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid to replace5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid,2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamidewas obtained (19%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ ¹HNMR (300 MHz, CDCl₃) δ 8.55 (s, 1H), 7.53 (d, J=10.2 Hz, 2H), 7.33-6.99(m, 4H), 6.54 (s, 1H), 6.38 (s, 1H), 5.22-5.01 (m, 2H), 4.75 (ABq, 2H),4.46 (t, J=8.8 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃)δ177.3, 161.9, 161.6, 160.9, 159.2, 143.2, 142.2, 136.8, 132.5, 129.2,124.1, 123.8, 120.8, 120.4, 119.7, 109.6, 92.8, 80.0, 72.5, 57.3, 37.4,28.7; MS (ES+) m/z 403.8 (M+1).

EXAMPLE 13.4 Synthesis ofN,N-dimethyl-2-[1(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide

Following the procedure as described in EXAMPLE 13.1 and makingnon-critical variations using2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid to replace5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(1′H)-yl)methyl]furan-2-carboxylicacid,N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamidewas obtained (3.0%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ8.09(s, 1H), 7.27-6.86 (m, 4H), 6.50 (s, 1H), 6.40 (s, 1H), 5.08 (ABq, 2H),4.82 (ABq, 2H), 4.52 (t, J=8.6 Hz, 2H), 3.29 (s, 3H), 3.06 (s, 3H), 2.97(t, J=8.6 Hz, 2H); MS (ES+) m/z 431.8 (M+1).

EXAMPLE 13.5 Synthesis ofN-cyclopropyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide

A solution of24(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1-yl)methyl)oxazole-4-carboxylicacid (0.41 g, 1.0 mmol), N-hydroxybenzotriazole (0.20 g, 1.5 mmol) and1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.29 g,1.5 mmol) in dichloromethane (10 mL) was stirred for 30 min, followed bythe addition of cyclopropylamine (0.8 mL). The solution was stirred atambient temperature for 16 h, diluted with dichloromethane (100 mL),washed with distilled water (2×50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo to dryness. The residue was purifiedby flash chromatography with ethyl acetate in hexanes (gradient: 50% to75%) to affordN-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide(0.40 g, 91%) as a colorless solid: mp 188-191° C.; ¹H NMR (300 MHz,CDCl₃) δ8.14 (s, 1H), 7.28-7.22 (m, 1H), 7.19 (d, J=6.8 Hz, 1H), 7.07(dd, J=7.4, 7.4 Hz, 1H), 6.85 (d, J=7.7 Hz, 2H), 6.49 (s, 1H), 6.16 (s,1H), 5.85 (ABq, 2H), 5.04 (ABq, 2H), 4.81 (ABq, 2H), 2.82 (m, 1H),0.85-0.77 (m, 2H), 0.64-0.58 (m, 2H); ¹³C NMR (75M Hz, CDCl₃) δ177.2,161.3, 158.1, 155.8, 149.0, 142.4, 141.8, 141.0, 136.6, 132.0, 129.1,124.15, 124.10, 119.2, 108.6, 103.0, 101.6, 93.7, 80.2, 58.2, 37.1,22.3, 6.60, 6.55; MS (ES+) m/z 446.2 (M+1).

EXAMPLE 13.6 Synthesis ofN-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide

Following the procedure as described in EXAMPLE 13.5 and makingnon-critical variations using isopropylamine to replacecyclopropylamine,N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamidewas obtained (17%) as a colorless solid: mp 182-183° C.; ¹H NMR (300MHz, CDCl₃) δ8.12 (s, 1H), 7.31-7.17 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz,1H), 6.88 (s, J=7.8 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 6.50 (s, 1H), 6.17(s, 1H), 5.85 (d, J=4.6 Hz, 2H), 5.05 (ABq, 2H), 4.82 (ABq, 2H), 4.20(m, 1H), 1.22 (d, J=6.5 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ177.2, 159.1,158.0, 155.8, 149.1, 142.4, 141.8, 141.0, 136.9, 132.0, 129.1, 124.2,119.2, 108.7, 103.0, 101.6, 93.7, 80.2, 58.2, 41.2, 37.1, 29.7, 22.7; MS(ES+) m/z 448.2 (M+1).

EXAMPLE 13.7 Synthesis ofN-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide

To a solution of(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)aceticacid (0.53 g, 1.50 mmol), 2-fluoroaniline (0.2 mL, 2.1 mmol) andtriethylamine (0.5 mL, 3.5 mmol) in chloroform (30 mL) was added2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.48 g, 1.94 mmol). Thereaction mixture was heated at reflux for 26 h, allowed to cool toambient temperature, diluted with ethyl acetate and washed sequentiallywith water, 10% w/v hydrochloric acid, water, 10% w/v aqueous sodiumhydroxide, water and brine. The organic phase was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by column chromatography and eluted with ethylacetate/hexanes (1/3) to affordN-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide(0.08 g, 12%): mp 117-119° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 8.24-8.22 (m, 1H), 8.05-7.90 (m, 1H), 7.33-6.95 (m, 6H),6.50-6.47 (m, 1H), 6.33-6.30 (m, 1H), 4.94-4.89 (m, 1H), 4.68-4.49 (m,4H), 4.17-4.09 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 164.6, 155.2,144.7, 141.3, 138.4, 131.9, 129.1, 125.6, 124.9, 121.8, 120.4, 115.0,114.8, 111.7, 108.9, 99.4, 80.0, 64.6, 63.8, 58.0, 45.1; MS (ES+) m/z446.8 (M+1).

EXAMPLE 13.8 Synthesis of2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid

Following the procedure as described in EXAMPLE 13 and makingnon-critical variations using methyl2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylateto replace methyl5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate,2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid was obtained (69%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ 13.13 (s, 1H), 8.70 (s, 1H), 7.74-7.71 (m, 1H), 7.40-7.34 (m, 1H),7.26-7.23 (m, 2H), 7.07-7.02 (m, 2H), 5.28-5.22 (m, 2H), 5.00-4.90 (m,2H), 2.39 (s, 3H); MS (ES+) m/z 417.8 (M+1).

EXAMPLE 13.9 Synthesis ofN,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide

A mixture of2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylicacid (0.32 g, 0.76 mmol), dimethylamine hydrochloride (0.13 g, 1.52mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.17 mmol),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.21 g,1.07 mmol), 4-methylmorpholine (0.23 mL, 2.07 mmol) and anhydrousN,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16h. The reaction mixture was concentrated in vacuo, and the residuerecrystallized from diethyl ether to affordN,N-dimethyl-2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide(0.23 g, 68%) as a colorless solid: mp 87-89° C. (diethyl ether); ¹H NMR(300 MHz, CDCl₃) δ 8.10 (s, 1H), 7.48-7.5 (m, 1H), 7.31-7.25 (m, 1H),7.14-7.11 (m, 1H), 7.05-6.95 (m, 3H), 5.28-5.06 (m, 3H), 4.87-4.84 (m,1H), 3.32 (s, 3H), 3.06 (s, 3H), 2.43 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ175.8, 164.0, 161.7, 158.2, 157.1, 154.9, 143.7, 141.3, 137.2, 130.1,129.5, 124.0, 123.9, 123.2, 118.0, 109.3, 108.6, 107.9, 81.3, 56.3,38.4, 37.5, 36.2, 9.8; MS (ES+) m/z 444.8 (M+1).

EXAMPLE 13.10 Synthesis of1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]

To a suspension of2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione(1.25 g, 2.70 mmol) in ethanol (25 mL) was added hydrazine monohydrate(0.70 mL, 8.2 mmol). The reaction mixture was stirred at ambienttemperature for 3 days, over which time a precipitate was deposited. Thesolid was collected by filtration and purified by column chromatographyand eluted with ethyl acetate/methanol/7 N methanolic ammonia (10/1/0.2)to afford1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneas a yellow oil: MS (ES+) m/z 336.9 (M+1).

EXAMPLE 13.11 Synthesis ofN-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide

To a solution of1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.20 g, 0.59 mmol) in anhydrous dichloromethane (10 mL) was addedtriethylamine (0.10 mL, 0.71 mmol) followed by2-(trifluoromethoxy)benzoyl chloride. The reaction mixture was stirredat ambient temperature for 20 h and concentrated in vacuo. The residuewas purified by column chromatography to affordN-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide(0.21 g, 67%) as a colorless foam: mp 65-70° C.; ¹H NMR (300 MHz, CDCl₃)δ 7.81 (dd, J=7.6, 1.7 Hz, 1H), 7.47 (ddd, J=9.4, 7.6, 1.5 Hz, 1H),7.39-7.30 (m, 3H), 7.20 (d, J=6.9 Hz, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 6.47 (s, 1H), 6.41 (s, 1H), 4.90 (d, J=9.0 Hz,1H), 4.67 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.6 Hz, 1H), 4.02-3.83 (m, 2H),3.58-3.33 (m, 2H), 2.99 (t, J=8.6 Hz, 2H), 2.05-2.01 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 179.0, 164.9, 161.9, 161.3, 145.7, 141.8, 132.8,131.8, 130.7, 129.3, 128.9, 127.3, 124.1, 123.7, 121.5, 120.3 (d,J_(C-F)=259.2 Hz), 120.0, 119.8, 118.7, 108.4, 93.3, 80.5, 72.4, 57.8,37.1, 36.1, 29.0, 27.0; MS (ES+) m/z 524.5 (M+1).

EXAMPLE 14 Synthesis of1′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A stirred mixture of1′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(2.4 g, 5.2 mmol), palladium on carbon (0.24 g, 10% wt) and 3 Mhydrochloric acid (5 mL) in absolute ethanol (50 mL) was hydrogenatedfor 6 h at 50 psi using a Parr hydrogenation apparatus. The mixture wasfiltered through celite and concentrated in vacuo to dryness. Theresidue was purified by flash chromatography with ethyl acetate inhexanes (25% to 50% gradient) to afford1-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.37 g, 78%) as a colorless solid: mp 171-174° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.28 (dd, J=7.7, 7.7 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.04(dd, J=7.5, 7.5 Hz, 1H), 6.97 (dd, J=7.8, 3.5 Hz, 1H), 6.49 (d, J=10.2Hz, 1H), 6.39 (d, J=1.4 Hz, 1H), 4.91 (dd, J=9.0, 0.5 Hz, 1H), 4.66 (dd,J=9.0, 0.6 Hz, 1H), 4.51 (dt, J=8.6, 1.0 Hz, 1H), 4.29-4.11 (m, 1H),3.90-3.66 (m, 2H), 3.07-2.87 (m, 2H), 2.41 (dd, J=32.9, 5.5 Hz, 1H),1.28 (dd, J=6.3, 1.1 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ179.2, 161.8(2), 161.3 (2), 142.6 (2), 132.9 (2), 128.7 (2), 123.9 (2), 123.5, 120.2(2), 120.0 (2), 118.8 (2), 108.9 (2), 93.2 (2), 80.6 (2), 72.4 (2), 66.5(2), 57.8 (2), 48.1 (2), 29.0 (2), 21.4; MS (ES+) m/z 338.0 (M+1).

EXAMPLE 14.1 Synthesis of1′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of1′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.19 mg, 0.56 mmol) in anhydrous tetrahydrofuran (10 mL) was addedsodium hydride (60% dispersion in mineral oil, 0.03 g, 0.71 mmol). Thesolution was stirred at ambient temperature for 30 min, thenbenzylbromide (0.14 g, 0.84 mmol) was added. The reaction mixture wasstirred for 16 h. The solution was cooled to ambient temperature,filtered and concentrated in vacuo to dryness. The residue was purifiedby flash chromatography with ethyl acetate in hexanes (25%) to afford1′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.20 g, 77%) as a colorless solid: mp 45-47° C.; ¹H NMR (300 MHz,CDCl₃) (diastereomers) δ7.30-6.97 (m, 9H), 6.38 (s, 1H), 6.33 (d, J=36.0Hz, 1H), 4.84 (dd, J=21.7, 8.9 Hz, 1H), 4.68-4.55 (m, 2H), 4.49 (dt,J=8.6, 0.8 Hz, 2H), 4.40 (dd, J=12.0, 3.8 Hz, 1H), 4.01-3.83 (m, 2H),3.80-3.68 (m, 1H), 2.88 (t, J=8.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)(diastereomers) δ178.1 (2), 161.7 (2), 161.3 (2), 143.0 (2), 138.3 (2),132.7, 128.6, 128.3 (2), 127.5 (2), 127.3, 123.6 (2), 123.2, 120.3 (2),119.8 (2), 118.9 (2), 109.7 (2), 93.2, 80.7 (2), 73.2, 72.8, 72.4, 70.9,70.7, 57.6, 46.1 (2), 29.0 (2), 17.7 (2); MS (ES+) m/z 428.0 (M+23).

EXAMPLE 14.2 Synthesis of1′-{(2S)-2-[(4-fluorobenzyl)oxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 14.1 and makingnon-critical variations using 4-fluorobenzyl bromide to replacebenzylbromide,1′-{(2S)-2-[(4-fluorobenzyl)oxy]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (70%) as a colorless solid: mp 55-60° C.; ¹H NMR (300 MHz,CDCl₃) δ7.30-7.20 (m, 1H), 7.17-6.97 (m, 5H), 6.93-6.84 (m, 2H), 6.38(s, 1H), 6.30 (d, J=36.9 Hz, 1H), 4.84 (dd, J=13.8, 8.9 Hz, 1H),4.65-4.53 (m, 2H), 4.49 (dt, J=8.6, 1.2 Hz, 2H), 4.36 (dd, J=11.8, 5.4Hz, 1H), 4.00-3.83 (m, 2H), 3.79-3.66 (m, 1H), 2.96-2.80 (m, 2H), 1.29(d, J=6.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.1, 162.2, 161.3, 143.0,134.0, 132.7, 129.0, 128.5, 123.7, 123.2, 120.2, 119.8, 118.8, 115.2,114.9, 93.2, 80.6, 73.3, 72.9, 72.4, 70.0, 57.6, 46.0, 29.0, 17.6; MS(ES+) m/z 445.8 (M+1).

EXAMPLE 14.3 Synthesis of1′-[(2S)-2-(pyridin-2-ylmethoxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 14.1 and makingnon-critical variations using 2-(bromomethyl)pyridine hydrobromide toreplace benzylbromide,1′-[(2S)-2-(pyridin-2-ylmethoxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (69%) as a colorless solid: mp 46-54° C.; ¹H NMR (300 MHz,CDCl₃) δ8.49-8.41 (m, 1H), 7.50 (m, 1H), 7.35-6.87 (m, 6H), 6.54-6.13(m, 2H), 4.94-4.80 (m, 1H), 4.80-4.67 (m, 1H), 4.66-4.32 (m, 4H),4.10-3.63 (m, 3H), 2.97-2.57 (m, 2H), 1.62-0.76 (m, 3H); ¹³C NMR (75MHz, CDCl₃) δ178.1, 161.7, 158.5, 148.8, 143.0, 136.6, 132.7, 128.6,123.7, 123.2, 122.2, 121.0, 120.3, 119.8, 118.8, 109.4, 93.1, 80.5,73.5, 72.3, 71.7, 57.6, 45.9, 28.9, 17.5; MS (ES+) m/z 428.74 (M+1).

EXAMPLE 14.4 Synthesis of1′-(3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal(0.34 g, 1.00 mmol) in tetrahydrofuran (10 mL) was added methylmagnesiumbromide (0.35 mL, 3 M diethyl ether solution, 1.05 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 3 h, quenched with saturatedammonium chloride solution, and extracted with ethyl acetate. Theorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography with ethyl acetate inhexanes (20% to 40% gradient) to afford1-(3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.21 g, 59%): mp 64-66° C. (diethyl ether/hexanes); ¹H NMR (300 MHz,CDCl₃) δ7.33-7.28 (m, 1H), 7.19-7.15 (m, 1H), 7.09-7.03 (m, 1H), 6.94(d, J=6.0 Hz, 1H), 6.46-6.40 (m, 2H), 4.92-4.87 (m, 1H), 4.69-4.62 (m,1H), 4.56-4.49 (m, 2H), 4.21-4.09 (m, 1H), 3.76-3.62 (m, 2H), 3.22 (brs, 1H), 3.03-2.95 (m, 2H), 1.88-1.63 (m, 2H), 1.24-1.19 (m, 3H); MS(ES+) m/z 352.1 (M+1).

EXAMPLE 14.5 Synthesis of1′-(4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

To a stirred solution of3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal(0.34 g, 1.00 mmol) in tetrahydrofuran (10 mL) were added cesiumfluoride (0.80 g, 5.26 mmol) and trifluoromethyltrimethylsilane (0.25mL, 1.69 mmol) at −78° C. The reaction mixture was stirred for 18 hwhile the temperature was slowly warmed to ambient temperature, quenchedwith methanol, stirred for 1 h at ambient temperature, and extractedwith ethyl acetate. The organic layer was washed with water, brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography with ethyl acetate in hexanes (20% to 40% gradient) togive1-(4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.24 g, 58%): mp 124-126° C. (diethyl ether/hexanes); ¹H NMR (300 MHz,CDCl₃) δ7.36-7.31 (m, 1H), 7.22-7.19 (m, 1H), 7.13-7.08 (m, 1H), 6.94(d, J=9.0 Hz, 1H), 6.45-6.41 (m, 2H), 4.89-4.70 (m, 1H), 4.67-4.63 (m,1H), 4.56-4.49 (m, 2H), 4.24-4.10 (m, 1H), 4.01-3.73 (m, 3H), 3.02-2.95(m, 2H), 2.11-2.05 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 179.5, 162.1,162.0, 161.4, 161.3, 141.5, 132.7, 129.1, 124.3, 124.0, 120.2, 119.6,118.8, 118.5, 108.4, 93.4, 80.3, 72.4, 67.8, 57.9, 36.2, 28.9; MS (ES+)m/z 405.7 (M+1).

EXAMPLE 15 Synthesis of3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal

To a solution of1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(2.00 g, 5.92 mmol) in dichloromethane (100 mL) was added Dess-Martinperiodinane (3.70 g, 8.46 mmol). The reaction mixture was stirred at 0°C. for 17 h, diluted with ethyl acetate, washed with 10% sodiumthiosulfate solution and saturated sodium bicarbonate solution andbrine. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo, the residue wassubjected to column chromatography with ethyl acetate in hexanes (20% to50% gradient) to afford3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal(1.74 g, 87%): MS (ES+) m/z 336.1 (M+1).

EXAMPLE 15.1 Synthesis of1′-{3-[(3-methylbutyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

To a solution of3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propanal(0.34 g, 1.00 mmol) and isoamylamine (0.20 mL, 1.72 mmol) in1,2-dichloroethane (20 mL) was added sodium triacetoxy borohydride (0.43g, 1.92 mmol). The reaction mixture was stirred at ambient temperaturefor 18 h. The reaction was quenched with saturated sodium bicarbonatesolution, and extracted with dichloromethane. The combined organicsolution was washed with water, brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated in vacuo, theresidue was subjected to column chromatography with ethyl acetate inhexanes (30% plus 1% 7 M ammonia in methanol) to afford1-{3-[(3-methylbutyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.37 g, 91%). The compound was then converted to its hydrogen chloridesalt (0.36 g) by treatment with hydrogen chloride (2 M solution indiethyl ether, 0.5 mL, 1.0 mmol): mp 98-101° C. (diethyl ether); ¹H NMR(300 MHz, DMSO-d₆)

8.79 (br s, 2H), 7.32-7.03 (m, 4H), 6.49 (s, 1H), 6.38 (s, 1H), 4.71(ABq, 2H), 4.49-4.43 (m, 2H), 3.82-3.65 (m, 2H), 2.94-2.82 (m, 6H),2.00-1.96 (m, 2H), 1.60-1.41 (m, 3H), 0.83 (d, J=9 Hz, 6H); MS (ES+) m/z407.2 (M+1).

EXAMPLE 15.2 Synthesis of1′-{3-[butyl(methyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 15.1 and makingnon-critical variations using N-methylbutylamine to replaceisoamylamine,1-{3-[butyl(methyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride was obtained (80%) as a colorless solid: mp 96-99° C.(diethyl ether); ¹H NMR (300 MHz, DMSO-d₆)

10.5 (br s, 1H), 7.35-7.00 (m, 4H), 6.49 (s, 1H), 6.37 (s, 1H), 4.71(ABq, 2H), 4.49-4.43 (m, 2H), 4.15 (br, 1H), 3.82-3.73 (m, 2H),3.12-2.89 (m, 6H), 2.69-2.63 (m, 2H), 2.12-1.97 (m, 2H), 1.66-1.52 (m,2H), 1.32-1.20 (m, 2H), 0.85 (t, J=6.0 Hz, 3H); MS (ES+) m/z 407.2(M+1).

EXAMPLE 15.3 Synthesis of1′-{3-[(2,2,2-trifluoroethyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 15.1 and makingnon-critical variations using 2,2,2-trifluoroethylamine to replaceisoamylamine,1′-{3-[(2,2,2-trifluoroethyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onehydrochloride was obtained (86%) as a colorless solid: mp 124-126° C.(diethyl ether); ¹H NMR (300 MHz, DMSO-d₆)

7.35-7.29 (m, 1H), 7.21-7.12 (m, 2H), 7.06-7.01 (m, 1H), 6.48 (s, 1H),6.37 (s, 1H), 4.71 (AB, 2H), 4.49-4.43 (m, 2H), 4.06-3.97 (m, 2H),3.87-3.70 (m, 2H), 3.04-2.89 (m, 4H), 2.11-2.00 (m, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ177.6, 161.6, 161.1, 142.6, 132.7, 129.2, 124.1, 123.4,120.9, 120.3, 119.5, 92.9, 80.3, 72.5, 57.3, 46.0, 37.5, 28.8, 24.3,22.5, 14.4; MS (ES+) m/z 419.1 (M+1).

EXAMPLE 15.4 Synthesis of3-{[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]amino}propanenitrilehydrochloride

Following the procedure as described in EXAMPLE 15.1 and makingnon-critical variations using 3-aminopropiontrile to replaceisoamylamine,3-{[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]amino}propanenitrilehydrochloride was obtained (61%) as a colorless solid: mp 214-216° C.(diethyl ether); ¹H NMR (300 MHz, DMSO-d₆)

7.33-7.29 (m, 1H), 7.20-7.12 (m, 2H), 7.04-6.99 (m, 1H), 6.45 (s, 1H),6.37 (s, 1H), 4.65 (ABq, 2H), 4.49-4.43 (m, 2H), 3.82-3.69 (m, 2H),3.01-2.76 (m, 8H), 1.92-1.79 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.5,161.6, 161.1, 142.8, 132.7, 129.2, 124.1, 123.4, 121.0, 120.3, 119.4,109.5, 92.9, 80.2, 72.5, 57.3, 45.4, 43.6, 37.8, 28.8, 25.8, 16.2; MS(ES+) m/z 390.1 (M+1).

EXAMPLE 16 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A stirred solution of4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.125 g, 0.3 mmol), 2-(dimethylamino)pyridine 5-boronic acid hydrate(0.08 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g,0.03 mmol), 2 M sodium carbonate (1 mL) in N,N-dimethylformamide (4 mL)was heated with stirring at 150° C. for 15 min in a microwave reactor.The solution was poured into distilled water (15 mL) and washed withethyl acetate (75 mL). The ethyl acetate layer was washed with brine(3×25 mL), dried on magnesium sulfate, filtered and concentrated invacuo to dryness. The residue was purified by flash chromatography withethyl acetate in hexanes (gradient: 30% to 60%) to afford4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(0.11 g, 73%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.53 (d,J=2.4 Hz, 1H), 7.33 (dd, J=7.8 Hz, 1H), 7.18 (dd, J=7.4, 4.7 Hz, 1H),6.77 (d, J=7.2 Hz, 1H), 6.71 (ddd, J=8.8, 2.4, 0.9 Hz, 1H), 6.51 (d,J=5.6 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.12 (d, J=0.9 Hz, 1H), 4.59-4.41(m, 3H), 4.33 (dd, J=9.4, 3.1 Hz, 1H), 4.23-4.08 (m, 1H), 3.89-3.55 (m,4H), 3.09-2.86 (m, 2H), 2.95 (s, 6H), 2.05-1.69 (m, 3H), 1.67-1.51 (m,1H); MS (ES+) m/z 484.1 (M+1).

EXAMPLE 16.1 Synthesis of4′-[(E)-2-(4-fluorophenyl)ethenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using trans-2-(4-fluorophenyl)vinyl boronic acidto replace 2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-[(E)-2-(4-fluorophenyl)ethenyl]-1-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (47%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.44-7.25 (m, 4H), 7.24-7.06 (m, 4H), 6.75 (d, J=16.4 Hz, 1H), 6.52 (s,1H), 6.48 (s, 1H), 4.78 (ABq, J=26.1, 9.6 Hz, 2H), 4.52-4.36 (m, 2H),4.23-4.09 (m, 1H), 3.90-3.54 (m, 4H), 2.92 (t, J=8.51, 8.51 Hz, 2H),2.04-1.69 (m, 3H), 1.68-1.53 (m, 1H); MS (ES+) m/z 484.1 (M+1).

EXAMPLE 16.2 Synthesis of4′-dibenzo[b,d]thiophen-4-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using dibenzothiophene-4-boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-dibenzo[b,d]thiophen-4-yl-t-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (45%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)(diastereomers) δ 8.53-8.02 (m, 2H), 8.02-7.70 (m, 1H), 7.67-7.21 (m,5H), 7.20-6.91 (m, 2H), 6.59 (s, 0.5H), 6.19 (s, 1H), 5.96 (s, 0.5H),5.28 (s, 0.5H), 5.01-4.76 (m, 0.5H), 4.68-4.31 (m, 2H), 4.29-4.13 (m,1H), 4.11-3.52 (m, 5H), 3.20-2.67 (m, 2H), 2.13-1.71 (m, 3H), 1.71-1.50(m, 1H); MS (ES+) m/z 546.0 (M+1).

EXAMPLE 16.3 Synthesis of4′-(1-benzothiophen-3-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using thianaphthene-3-boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-(1-benzothiophen-3-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (49%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.86(d, J=7.2 Hz, 1H), 7.57-6.70 (m, 7H), 6.48-6.31 (br s, 1H), 5.76 (br s,1H), 4.52-4.09 (m, 5H), 3.93-3.57 (m, 4H), 2.97-2.66 (m, 2H), 2.05-1.71(m, 3H), 1.70-1.54 (m, 1H); MS (ES+) m/z 496.1 (M+1).

EXAMPLE 16.4 Synthesis of4′-(1-methyl-1H-indol-5-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolen-2-yl)-1H-indole toreplace 2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-(1-methyl-1H-indol-5-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆) δ7.34(dd, J=7.8, 7.82 Hz, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.23-7.14 (m, 2H),6.85 (d, J=7.2 Hz, 1H), 6.73-6.71 (m, 1H), 6.63-6.57 (m, 2H), 6.09 (d,J=3.0 Hz, 1H), 6.03 (s, 1H), 4.62-4.46 (m, 2H), 4.40 (dd, J=9.2, 2.7 Hz,1H), 4.26-4.12 (m, 1H), 4.09 (dd, J=9.2, 1.1 Hz, 1H), 3.92-3.56 (m, 4H),3.79 (s, 3H), 3.16-2.90 (m, 2H), 2.04-1.71 (m, 3H), 1.69-1.54 (m, 1H);MS (ES+) m/z 493.2 (M+1).

EXAMPLE 16.5 Synthesis of4′-[3,5-bis(trifluoromethyl)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using 3,5-bis(trifluoromethyl)phenyl boronicacid to replace 2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-[3,5-bis(trifluoromethyl)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (40%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.73(s, 1H), 7.36 (dd, J=7.9, 7.9 Hz, 1H), 7.26-7.23 (m, 2H), 7.19 (dd,J=7.2, 7.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 6.53 (s, 1H), 5.90 (s, 1H),4.70 (d, J=8.9 Hz, 1H), 4.51 (t, J=8.9, 8.9 Hz, 2H), 4.39 (d, J=9.1 Hz,1H), 4.34-4.23 (m, 1H), 4.05-3.67 (m, 4H), 2.98 (t, J=8.5 Hz, 2H),2.15-1.83 (m, 3H), 1.79-1.65 (m, 1H); MS (ES+) m/z 576.1 (M+1).

EXAMPLE 16.6 Synthesis of4′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using p-phenoxyphenyl boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-onewas obtained (35%) as a colorless solid: ¹H NMR (300 MHz, DMSO-d₆)δ7.42-7.30 (m, 3H), 7.22 (dd, J=7.6, 4.3 Hz, 1H), 7.11 (dd, J=7.4, 7.4Hz, 1H), 6.95 (d, J=8.4 Hz, 2H), 6.82 (d, J=7.6 Hz, 1H), 6.78-6.70 (m,4H), 6.50 (d, J=5.8 Hz, 1H), 6.03 (s, 1H), 4.54-4.33 (m, 4H), 4.25-4.10(m, 1H), 3.90-3.55 (m, 4H), 3.08-2.83 (m, 2H), 2.05-1.70 (m, 3H),1.68-1.54 (m, 1H); MS (ES+) m/z 532.1 (M+1).

EXAMPLE 16.7 Synthesis of4′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using p-(2-methylpropoxy)phenyl boronic acid toreplace 2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (34%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.31(dd, J=7.8, 7.8 Hz, 1H), 7.08 (ddd, J=10.3, 7.9, 0.9 Hz, 1H), 6.88 (d,J=7.7 Hz, 1H), 6.71-6.62 (m, 4H), 6.58 (s, 1H), 6.18-6.15 (m, 1H),4.68-4.48 (m, 3H), 4.39-4.23 (m, 2H), 4.07-3.57 (m, 6H), 3.13-2.92 (m,2H), 2.14-1.81 (m, 4H), 1.80-1.66 (m, 1H), 1.00 (dd, J=6.7, 1.2 Hz, 6H);MS (ES+) m/z 512.2 (M+1).

EXAMPLE 16.8 Synthesis of4′-(4-butoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using p-butoxylphenyl boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-(4-butoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (34%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.31(dd, J=7.8, 7.8 Hz, 1H), 7.14-7.03 (m, 1H), 6.88 (d, J=7.7 Hz, 1H),6.72-6.61 (m, 4H), 6.58 (s, 1H), 6.16 (s, 1H), 4.69-4.46 (m, 3H),4.39-4.23 (m, 2H), 4.09-3.56 (m, 6H), 3.14-2.92 (m, 2H), 2.14-1.82 (m,3H), 1.81-1.65 (m, 3H), 1.55-1.40 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS(ES+) m/z 512.1 (M+1).

EXAMPLE 16.9 Synthesis of4′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using p-methoxyphenyl boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (41%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.32(dd, J=7.8, 7.8 Hz, 1H), 7.19 (dd, J=7.2, 4.8 Hz, 1H), 6.78 (d, J=7.1Hz, 1H), 6.70-6.59 (m, 4H), 6.52 (d, J=5.2 Hz, 1H), 6.11 (s, 1H),4.58-4.40 (m, 3H), 4.26-4.09 (m, 2H), 3.90-3.54 (m, 7H), 3.09-2.87 (m,2H), 2.05-1.70 (m, 3H), 1.68-1.54 (m, 1H); MS (ES+) m/z 469.9 (M+1).

EXAMPLE 16.10 Synthesis of4′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using pyrimidine-5-boronic acid to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,4′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (38%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ9.08(s, 1H), 8.12 (d, J=1.16 Hz, 1H), 7.38 (dd, J=7.8, 7.8 Hz, 2H),7.24-7.16 (m, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.58-6.53 (m, 1H), 6.04 (s,1H), 4.72 (dd, J=9.3, 1.3 Hz, 1H), 4.63-4.46 (m, 2H), 4.39 (dd, J=9.3,1.3 Hz, 1H), 4.35-4.23 (m, 1H), 4.06-3.65 (m, 4H), 3.01 (t, J=8.6 Hz,2H), 2.16-1.84 (m, 3H), 1.79-1.63 (m, 1H); MS (ES+) m/z 442.0 (M+1).

EXAMPLE 16.11 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using4′-bromo-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-onewas obtained (73%) as a colorless solid: mp 223-225° C.; ¹H NMR (300MHz, CDCl₃) δ 7.82-7.77 (m, 1H), 7.32 (dd, J=7.8, 7.8 Hz, 1H), 7.25-7.23(m, 1H), 6.93 (dd, J=16.6, 7.8 Hz, 2H), 6.78-6.71 (m, 1H), 6.65-6.58 (m,1H), 6.53 (s, 1H), 6.44 (d, J=2.5 Hz, 1H), 6.28-6.16 (m, 2H), 5.19 (d,J=16.1 Hz, 1H), 4.78 (d, J=16.2 Hz, 1H), 4.71 (d, J=9.2 Hz, 1H),4.64-4.50 (m, 2H), 4.47 (d, J=9.2 Hz, 1H), 3.07-2.97 (m, 8H); MS (ES+)m/z 548.0 (M+1).

EXAMPLE 16.12 Synthesis of1′-[(5-chloro-2-thienyl)methyl]-4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

A round bottom flask (25 mL) equipped with condenser was charged with4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.18 g, 0.50 mmol), 6-(dimethylamino)pyridin-3-ylboronic acid (0.084 g,0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 10 mol%). The flask was flushed with nitrogen for 5 min, then anhydrousdioxane (7 mL) and 2 M sodium carbonate (0.5 mL). The reaction mixturewas heated at reflux for 16 h, cooled to ambient temperature and thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate (20 mL), washed with saturated ammonium chloride (10 mL),brine (10 mL), dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby flash column chromatography with ethyl acetate in hexanes (70%) toafford1-[(5-chloro-2-thienyl)methyl]-4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.10 g, 70%) as a colourless solid: mp 215-218° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.54 (d, J=2.0 Hz, 1H), 7.34 (dd, J=7.8, 7.8 Hz, 1H), 7.22 (d,J=7.2 Hz, 1H), 7.13 (d, J=3.8 Hz, 1H), 6.98 (d, J=3.8 Hz, 1H), 6.80 (d,J=8.0 Hz, 1H), 6.74 (dd, J=8.8, 2.5 Hz, 1H), 6.38 (s, 1H), 6.33 (d,J=8.8 Hz, 1H), 6.20 (s, 1H), 5.93 (d, J=18.0 Hz, 2H), 5.05 (ABq, 2H),4.44 (ABq, 2H), 2.95 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.5, 158.4,156.0, 148.9, 147.1, 142.3, 142.0, 138.4, 137.6, 137.3, 129.6, 129.4,128.2, 127.9, 127.1, 126.1, 122.1, 121.1, 109.0, 104.7, 102.8, 101.9,93.7, 77.9, 58.2, 38.1, 31.2; MS (ES+) m/z 534.1 (M+1), 532.2 (M+1).

EXAMPLE 16.13 Synthesis of1′-[(5-chloro-2-thienyl)methyl]-4′-(3-furyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′1-1)-one

Following the procedure as described in EXAMPLE 16.12 and makingnon-critical variations using 3-furanboronic acid to replace6-(dimethylamino)pyridin-3-ylboronic acid,1-[(5-chloro-2-thienyl)methyl]-4′-(3-furyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas obtained (95%) as a colorless solid: mp 166-168° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.57 (dd, J=1.7, 1.7 Hz, 1H), 7.34 (dd, J=7.9, 7.9 Hz,1H), 7.20 (d, J=7.2 Hz, 1H), 7.11 (d, J=3.8 Hz, 1H), 7.04 (s, 1H),6.99-6.96 (m, 2H), 6.77 (s, 1H), 6.19 (s, 1H), 6.03 (dd, J=1.7, 0.8 Hz,1H), 5.93 (d, J=2.7 Hz, 2H), 5.04 (ABq, 2H), 4.55 (ABq, 2H); ¹³C NMR (75MHz, DMSO-d₆) δ177.4, 156.2, 149.1, 143.8, 142.9, 142.0, 140.6, 138.4,130.7, 129.6, 128.2, 127.7, 127.0, 125.6, 122.9, 120.8, 111.4, 109.3,102.9, 102.0, 93.9, 77.6, 58.1, 39.1; MS (ES+) m/z 480.3 (M+1), 478.3(M+1).

EXAMPLE 16.14 Synthesis of4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a suspended mixture of4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.00g, 2.78 mmol), 6-(dimethylamino)pyridin-3-ylboronic acid (0.69 g, 4.17mmol) and tetrakis(triphenylphosphine)palladium (0) (0.32 g, 0.28 mmol)in N,N-dimethylformamide (30 mL) was added aqueous 2 M sodium carbonate(2.8 mL, 5.6 mmol). The reaction mixture was refluxed for 3 h. The solidwas filtered and washed with ethyl acetate (40 mL). The filtrate wasconcentrated in vacuo to dryness. The residue was purified by columnchromatography with ethyl acetate in hexanes (20% to 50% gradient) toafford4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.60 g, 54%) as a white powder: mp>245° C. (ethyl acetate); ¹H NMR (300MHz, DMSO-d₆) δ10.69 (s, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.29 (dd, J=7.8,7.8 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.79-6.74 (m, 2H), 6.40-6.35 (m,3H), 5.95 (d, J=19.9 Hz, 2H), 4.52 (d, J=9.3 Hz, 1H), 4.36 (d, J=9.3 Hz,1H), 2.99 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.8, 157.9, 155.5,148.1, 146.6, 142.2, 141.5, 137.0, 136.8, 129.8, 128.9, 124.4, 121.9,121.2, 109.0, 104.2, 102.5, 101.3, 93.1, 77.5, 58.2, 37.6; MS (ES+) m/z402.3 (M+1).

EXAMPLE 16.15 Synthesis of1′-methyl-4′-(2-oxo-2H-chromen-7-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16 and makingnon-critical variations using4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chromen-2-one(Isihiyama et al., Tetrahedron Lett. (1997) 38:3447-3450) to replace2-(dimethylamino)pyridine 5-boronic acid hydrate,1-methyl-4′-(2-oxo-2H-chromen-7-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (55%) as an off-white solid: mp 228-229° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.71-7.63 (m, 1H), 7.42-7.36 (m, 1H),7.32-7.27 (m, 1H), 6.99-6.94 (m, 1H), 6.93-6.86 (m, 1H), 6.80-6.74 (m,1H), 6.69-6.64 (m, 1H), 6.43-6.36 (m, 1H), 6.34-6.29 (m, 1H), 6.00-5.94(m, 1H), 4.67-4.60 (m, 1H), 4.35-4.04 (m, 5H), 3.32 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 177.5, 160.5, 155.3, 153.1, 145.0, 143.2, 143.1, 142.1,138.3, 138.2, 129.8, 128.9, 126.9, 124.8, 124.5, 121.1, 117.7, 117.1,116.6, 111.2, 108.2, 98.8, 78.4, 64.5, 63.9, 58.3, 26.9; MS (ES+) m/z453.8 (M+1).

EXAMPLE 16.16 Synthesis of1′-methyl-4′-(2-oxopyrrolidin-1-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a degassed solution of4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.00 g, 2.57 mmol), 2-pyrrolidinone (0.30 mL, 3.9 mmol), potassiumcarbonate (0.71 g, 5.1 mmol) and rac-trans-N,N′dimethylcyclohexane-1,2-diamine (0.10 mL, 0.63 mmol) in dimethylsulfoxide (20 mL) was added copper(I) iodide (0.06 g, 0.31 mmol). Themixture was stirred at 150° C. under nitrogen for 48 h, allowed to coolto ambient temperature, diluted with ethyl acetate and washedsequentially with 10% v/v ammonium hydroxide, water and brine. Theorganic phase was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was subjected to columnchromatography and eluted with ethyl acetate to afford1-methyl-4′-(2-oxopyrrolidin-1-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.28 g, 28%): mp 256-258° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.38-7.32 (m, 1H), 6.90-6.87 (m, 1H), 6.78-6.76 (m, 1H), 6.44(s, 1H), 6.23 (s, 1H), 4.84 (ABq, 2H), 4.18-4.06 (m, 4H), 3.34-3.24 (m,4H), 2.56-2.27 (m, 3H), 1.98-1.80 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.1, 175.9, 155.6, 144.7, 143.9, 138.1, 135.5, 131.4, 130.3, 122.8,119.8, 111.5, 108.5, 98.8, 78.3, 64.5, 63.9, 57.7, 50.6, 30.6, 27.1,18.8; MS (ES+) m/z 393.1 (M+1).

EXAMPLE 16.17 Synthesis of1′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a degassed solution of4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.00 g, 2.57 mmol), morpholine (0.34 mL, 3.9 mmol), sodiumtert-butoxide (0.45 g, 4.7 mmol) and9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.30 g, 0.52 mmol) intoluene (40 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.24g, 0.26 mmol). The mixture was stirred at reflux under nitrogen for 48h, allowed to cool to ambient temperature, diluted with ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo. The residue wassubjected to column chromatography eluted with ethyl acetate/hexanes(1/1) to afford1′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.04 g, 4%): mp 246-249° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 7.35-7.29 (m, 1H), 6.94-6.87 (m, 2H), 6.42 (s, 1H), 6.17 (s,1H), 4.75 (ABq, 2H), 4.14-4.02 (m, 4H), 3.30 (t, J=4.2 Hz, 4H), 3.12 (s,3H), 2.52-2.27 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.8, 155.6, 149.9,144.7, 144.3, 137.6, 130.3, 127.1, 121.6, 117.1, 111.3, 106.4, 98.6,77.8, 66.7, 64.6, 64.0, 57.7, 53.0, 27.0; MS (ES+) m/z 395.0 (M+1).

EXAMPLE 16.18 Synthesis of1′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a degassed solution of4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.00 g, 2.57 mmol), 2-hydroxypyridine (0.49 g, 5.2 mmol), potassiumcarbonate (1.10 g, 7.95 mmol) and 8-hydroxyquinoline (0.15 g, 1.04 mmol)in dimethyl sulfoxide (30 mL) was added copper(I) iodide (0.10 g, 0.52mmol). The reaction mixture was heated at 150° C. for 72 h, allowed tocool to ambient temperature, diluted with dichloromethane, washedsequentially with 10% v/v ammonium hydroxide, water and brine, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography and eluted with ethyl acetate/hexanes (1/1) to afford1′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.02 g, 3%): mp 212-214° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.99-7.96 (m, 1H), 7.57-7.50 (m, 1H), 7.38-7.34 (m, 1H),6.88-6.76 (m, 3H), 6.69-6.66 (m, 1H), 6.18 (s, 2H), 4.73 (s, 2H),4.11-4.01 (m, 4H), 3.28 (3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.3, 155.3,149.9, 144.5, 144.2, 139.0, 137.7, 129.9, 123.6, 118.9, 117.9, 111.6,105.3, 98.7, 78.9, 64.4, 63.7, 57.4, 27.0; MS (ES+) m/z 403.0 (M+1).

EXAMPLE 16.19 Synthesis of4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a degassed solution of4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(11.58 g, 30.0 mmol), benzophenone imine (7.8 mL, 46 mmol) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (5.64 g, 9.00 mmol) intoluene (250 mL) was added tris(dibenzylideneacetone)dipalladium(0)(2.75 g, 3.00 mmol) followed by sodium tert-butoxide (5.40 g, 56.2mmol). The mixture was stirred at reflux under nitrogen for 20 h andfiltered through a pad of diatomaceous earth. The filtrate wasconcentrated in vacuo and the residue was dissolved in tetrahydrofuran(100 mL). 10% w/v hydrochloric acid (20 mL) was added and the mixturewas stirred at ambient temperature for 5 h and concentrated in vacuo toremove most of the tetrahydrofuran. The mixture was neutralized with 10%w/v aqueous sodium hydroxide and extracted with dichloromethane (3×150mL). The combined organic extracts was washed with water and brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was recrystallized sequentially fromethyl acetate/hexanes followed by methanol to afford4′-amino-t-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(8.90 g, 90%): mp 252-254° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.11-7.05 (m, 1H), 6.46 (s, 1H), 6.36-6.31 (m, 3H), 4.75 (ABq,2H), 4.19-4.06 (m, 4H), 3.59 (br s, 2H), 3.23 (3H); MS (ES+) m/z 325.0(M+1).

EXAMPLE 16.20 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide

To a solution of4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(700 mg, 1.72 mmol) in dichloromethane (50 mL) and pyridine (5 mL) wasadded cyclobutanecarbonyl chloride (0.17 mL, 1.48 mmol) at 0° C. Thereaction mixture was stirred at ambient temperature for 18 h, dilutedwith dichloromethane (150 mL), washed sequentially with water, 10% w/vhydrochloric acid, water and brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo. The residue wassubjected to column chromatography and eluted with ethyl acetate/hexanes(1/3) to affordN-(1-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide(0.50 g, 71%): mp 234-236° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 8.15 (s, 1H), 7.32-7.26 (m, 1H), 7.11-7.08 (m, 1H), 6.94-6.91(m, 1H), 6.43 (s, 1H), 6.17 (s, 1H), 4.68 (ABq, 2H), 4.13-4.05 (m, 4H),3.15 (s, 3H), 2.96-2.90 (m, 1H), 2.05-1.64 (m, 6H); ¹³C NMR (75 MHz,DMSO-d₆) δ 176.6, 173.5, 155.1, 144.6, 144.3, 138.3, 134.6, 129.5,125.3, 120.8, 119.4, 112.0, 106.8, 98.8, 78.2, 64.6, 64.0, 57.1, 27.1,25.0, 24.9, 17.9; MS (ES+) m/z 406.9 (M+1).

EXAMPLE 16.21 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-2-(trifluoromethyl)benzamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using 2-(trifluoromethyl)benzoyl chloride toreplace cyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-2-(trifluoromethyl)benzamidewas obtained (66%): mp 241-243° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 8.02-7.98 (m, 1H), 7.74-7.70 (m, 1H), 7.62-7.56 (m, 2H),7.41-7.33 (m, 2H), 7.28-7.23 (m, 1H), 6.76-6.73 (m, 1H), 6.33 (s, 1H),6.03 (s, 1H), 4.71 (ABq, 2H), 4.18-4.08 (m, 4H), 3.29 (s, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 175.9, 165.7, 153.8, 145.0, 142.8, 139.4, 134.3,131.9, 130.3, 130.0, 127.5, 126.7, 120.7, 118.0, 116.5, 112.1, 105.2,99.3, 78.8, 64.5, 63.8, 57.2, 27.1; MS (ES+) m/z 497.0 (M+1).

EXAMPLE 16.22 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)methanesulfonamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using methanesulfonyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)methanesulfonamidewas obtained (89%): mp 184-186° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.34-7.25 (m, 2H), 6.75-6.71 (m 1H), 6.61 (s, 1H), 6.56(br s, 1H), 6.34 (s, 1H), 4.70 (ABq, 2H), 4.19-4.06 (m, 4H), 3.29 (s,3H), 2.35 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.5, 154.1, 145.3, 143.2,139.6, 133.9, 130.3, 121.1, 118.5, 114.9, 111.6, 105.2, 100.4, 78.7,64.4, 63.9, 57.0, 38.7, 27.1; MS (ES+) m/z 402.9 (M+1).

EXAMPLE 16.23 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclohexanecarboxamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using cyclohexanecarbonyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclohexanecarboxamidewas obtained (23%): mp 96-98° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.99-7.95 (m, 1H), 7.31-7.25 (m 1H), 7.04 (br s, 1H),6.67-6.64 (m, 1H), 6.53 (s, 1H), 6.34 (s, 1H), 4.74 (ABq, 2H), 4.21-4.10(m, 4H), 3.26 (s, 3H), 2.04-1.69 (m, 11H); ¹³C NMR (75 MHz, CDCl₃) δ176.3, 174.5, 154.4, 145.3, 142.8, 139.3, 135.1, 129.8, 119.1, 118.0,115.8, 112.3, 104.2, 99.4, 78.6, 64.5, 63.8, 57.1, 46.7, 29.4, 29.0,27.0, 25.6; MS (ES+) m/z 435.0 (M+1).

EXAMPLE 16.24 Synthesis ofN-(1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopentanecarboxamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using cyclopentanecarbonyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopentanecarboxamidewas obtained (52%): mp 196-198° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.98-7.94 (m, 1H), 7.30-7.24 (m 1H), 7.09 (br s, 1H),6.67-6.64 (m, 1H), 6.53 (s, 1H), 6.32 (s, 1H), 4.74 (ABq, 2H), 4.20-4.09(m, 4H), 3.26 (s, 3H), 2.45-2.39 (m, 1H), 1.89-1.51 (m, 8H); ¹³C NMR (75MHz, CDCl₃) δ 176.2, 174.7, 154.3, 145.2, 142.7, 139.3, 135.1, 129.8,119.2, 118.2, 115.9, 112.2, 104.2, 99.4, 78.4, 64.5, 63.8, 57.1, 46.7,30.1, 29.9, 27.0, 25.9; MS (ES+) m/z 421.1 (M+1).

EXAMPLE 16.25 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using acetyl chloride to replacecyclobutanecarbonyl chloride,N-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamidewas obtained (27%): mp 182-184° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.89-7.85 (m, 1H), 7.31-7.24 (m, 1H), 7.14 (br s, 1H),6.69-6.65 (m 1H), 6.53 (s, 1H), 6.32 (br s, 1H), 4.74 (ABq, 2H),4.19-4.10 (m, 4H), 3.27 (s, 3H), 1.95 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ176.0, 168.5, 154.0, 145.1, 142.6, 139.4, 134.7, 129.7, 119.9, 116.1,112.1, 104.5, 99.2, 78.6, 64.5, 63.8, 57.1, 27.0, 24.3; MS (ES+) m/z367.0 (M+1).

EXAMPLE 16.26 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopropanecarboxamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using cyclopropanecarbonyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopropanecarboxamidewas obtained (78%): mp 266-268° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.93-7.89 (m, 1H), 7.33 (br s, 1H), 7.28-7.23 (m, 1H),6.67-6.63 (m 1H), 6.53 (s, 1H), 6.33 (s, 1H), 4.77 (ABq, 2H), 4.20-4.10(m, 4H), 3.27 (s, 3H), 1.26-1.17 (m, 1H), 0.99-0.73 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 176.1, 172.1, 154.1, 145.1, 142.6, 139.4, 135.0, 129.7,119.4, 118.3, 116.0, 112.1, 104.5, 99.3, 78.5, 64.5, 63.8, 57.2, 27.0,15.6, 8.1, 8.0; MS (ES+) m/z 393.0 (M+1).

EXAMPLE 16.27 Synthesis ofN-(1-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)benzamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using benzoyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)benzamidewas obtained (60%): mp 192-194° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 8.21-8.18 (m, 1H), 7.76 (br s, 1H), 7.63-7.59 (m, 2H),7.53-7.32 (m, 4H), 6.73-6.70 (m 1H), 6.46 (s, 1H), 6.38 (s, 1H), 4.80(ABq, 2H), 4.17-4.08 (m, 4H), 3.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ176.3, 165.4, 154.2, 145.2, 143.0, 139.4, 135.0, 134.0, 132.1, 130.0,128.6, 127.0, 119.4, 117.9, 115.9, 112.2, 104.6, 99.8, 78.5, 64.5, 63.8,60.4, 57.2, 27.0; MS (ES+) m/z 428.9 (M+1).

EXAMPLE 16.28 Synthesis of2-methoxy-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using methoxyacetyl chloride to replacecyclobutanecarbonyl chloride,2-methoxy-N-(1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamidewas obtained (70%): mp 237-239° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 8.07 (br s, 1H), 7.98-7.95 (m, 1H), 7.33-7.27 (m, 1H),6.71-6.67 (m 1H), 6.50 (s, 1H), 6.29 (s, 1H), 4.73 (ABq, 2H), 4.20-4.09(m, 4H), 3.89 (ABq, 2H), 3.31 (s, 3H), 3.25 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 176.7, 168.2, 155.2, 145.1, 143.4, 138.7, 134.0, 129.8, 119.4,117.5, 116.2, 111.8, 104.8, 99.7, 78.1, 71.9, 64.5, 63.8, 59.1, 57.1,26.9; MS (ES+) m/z 396.9 (M+1).

EXAMPLE 16.29 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using propionyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamidewas obtained (42%): mp 224-226° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.93-7.90 (m, 1H), 7.31-7.23 (m, 1H), 7.09 (br s, 1H),6.68-6.64 (m, 1H), 6.52 (s, 1H), 6.32 (s, 1H), 4.73 (ABq, 2H), 4.20-4.08(m, 4H), 3.31 (s, 3H), 3.27 (s, 3H), 2.28-2.07 (m, 2H), 1.07 (t, J=7.5Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.7, 172.2, 154.1, 145.1, 142.7,139.4, 134.8, 129.8, 119.7, 118.2, 116.1, 112.1, 104.3, 99.3, 78.5,64.5, 63.8, 57.1, 30.6, 27.0, 9.2; MS (ES+) m/z 381.0 (M+1).

EXAMPLE 16.30 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)pentanamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using valeryl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)pentanamidewas obtained (30%): mp 182-183° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.96-7.92 (m, 1H), 7.31-7.23 (m, 1H), 7.09 (br s, 1H),6.68-6.64 (m, 1H), 6.52 (s, 1H), 6.33 (s, 1H), 4.74 (ABq, 2H), 4.19-4.10(m, 4H), 3.27 (s, 3H), 2.19-2.05 (m, 2H), 1.55-1.45 (m, 2H), 1.32-1.22(m, 2H), 0.88 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 171.6,154.2, 145.1, 142.7, 139.4, 134.9, 129.8, 119.5, 118.2, 116.0, 112.2,104.3, 99.3, 78.6, 64.5, 63.8, 57.1, 37.5, 27.3, 27.0, 22.2, 13.7; MS(ES+) m/z 409.0 (M+1).

EXAMPLE 16.31 Synthesis of2,2-dimethyl-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using trimethylacetyl chloride to replacecyclobutanecarbonyl chloride,2,2-dimethyl-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamidewas obtained (47%): mp 182-184° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.87 (br s, 1H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 1H),6.94-6.91 (m, 1H), 6.43 (s, 1H), 6.22 (s, 1H), 4.70 (ABq, 2H), 4.15-4.01(m, 4H), 3.15 (s, 3H), 0.97 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 177.0,176.7, 155.0, 144.7, 144.4, 138.3, 135.0, 129.6, 124.3, 120.2, 119.1,112.2, 106.6, 99.1, 78.1, 64.6, 64.0, 57.1, 39.2, 27.3, 27.1; MS (ES+)m/z 409.0 (M+1).

EXAMPLE 16.32 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)hexanamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using hexanoyl chloride to replacecyclobutanecarbonyl chloride,N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)hexanamidewas obtained (67%): mp 151-153° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.96-7.92 (m, 1H), 7.31-7.23 (m, 1H), 7.10 (br s, 1H),6.68-6.64 (m, 1H), 6.52 (s, 1H), 6.32 (s, 1H), 4.74 (ABq, 2H), 4.20-4.09(m, 4H), 3.27 (s, 3H), 3.21-2.02 (m, 2H), 1.56-1.47 (m, 2H), 1.30-1.23(m, 4H), 0.86 (t, J=6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 171.6,154.1, 145.1, 142.6, 139.4, 134.9, 129.8, 119.5, 118.2, 116.0, 112.2,104.3, 99.3, 78.5, 64.5, 63.8, 57.1, 37.7, 31.3, 27.0, 24.9, 22.3, 13.9;MS (ES+) m/z 423.0 (M+1).

EXAMPLE 16.33 Synthesis ofN-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)heptanamide

Following the procedure described in EXAMPLE 16.20 and makingnon-critical variations using heptanoyl chloride to replacecyclobutanecarbonyl chloride,N-(1-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)heptanamidewas obtained (46%): mp 123-124° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.96-7.92 (m, 1H), 7.31-7.23 (m, 1H), 7.10 (br s, 1H),6.68-6.64 (m, 1H), 6.52 (s, 1H), 6.32 (s, 1H), 4.74 (ABq, 2H), 4.19-4.05(m, 4H), 3.27 (s, 3H), 3.21-2.03 (m, 2H), 1.53-1.47 (m, 2H), 1.35-1.14(m, 6H), 0.86 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 176.1, 171.7,154.1, 145.1, 142.6, 139.3, 134.9, 129.8, 119.5, 118.2, 116.0, 112.2,104.3, 99.3, 78.5, 64.5, 63.8, 57.1, 37.8, 31.4, 28.8, 27.0, 25.2, 22.4,14.0; MS (ES+) m/z 437.1 (M+1).

EXAMPLE 16.34 Synthesis of2-(2-methoxyethoxy)-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide

Following the procedure as described in EXAMPLE 16.20 and makingnon-critical variations using 2-(2-methoxyethoxy)acetyl chloride toreplace cyclobutanecarbonyl chloride,2-(2-methoxyethoxy)-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-4′-yl)acetamidewas obtained (77%): mp 122-123° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 8.08 (br s, 1H), 7.85-7.81 (m, 1H), 7.33-7.26 (m, 1H),6.72-6.68 (m, 1H), 6.46 (s, 1H), 6.26 (s, 1H), 4.78 (ABq, 2H), 4.18-4.06(m, 4H), 3.99 (ABq, 2H), 3.65-3.40 (m, 4H), 3.32 (s, 3H), 3.24 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 176.7, 168.5, 155.1, 144.9, 143.4, 138.7,133.8, 129.8, 120.4, 117.9, 117.2, 111.7, 105.1, 99.6, 77.8, 71.7, 70.8,64.5, 63.8, 58.9, 57.1, 26.9; MS (ES+) m/z 441.1 (M+1).

EXAMPLE 16.35 Synthesis of1-hexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-4′-yl)urea

To a stirred solution of4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.33 g, 1.00 mmol) in 1,4-dioxane (20 mL) was added trichloromethylchloroformate (0.14 mL, 1.2 mmol). The reaction mixture was heated at65° C. for 24 h, allowed to cool to ambient temperature and concentratedin vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and theresultant solution was cooled to 0° C. in an ice bath. n-Hexylamine(0.40 mL, 3.0 mmol) and triethylamine (0.70 mL, 5.0 mmol) were added.The reaction mixture was allowed to warm to ambient temperature, stirredfor 24 h and concentrated in vacuo. The residue was dissolved in ethylacetate and washed with water (4×150 mL). The organic phase was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate/hexanes to afford1-hexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea(0.294 g, 64%) as a pale brown solid: mp 154-155° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.78-7.75 (m, 1H), 7.30-7.25(m, 1H), 6.63-6.60 (m, 1H), 6.52 (s, 1H), 6.34 (s, 1H), 6.09 (s, 1H),4.76 (ABq, 2H), 4.22-4.11 (m, 5H), 3.28 (s, 3H), 3.14-3.00 (m, 2H),1.48-1.41 (m, 2H), 1.32-1.25 (m, 6H), 0.89 (t, J=6.7 Hz, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 176.3, 154.6, 154.2, 145.1, 142.8, 139.4, 135.9,129.8, 119.0, 118.3, 115.8, 112.2, 103.3, 99.3, 78.2, 64.5, 63.8, 57.1,40.5, 31.5, 29.8, 27.0, 26.4, 22.5, 14.0; MS (ES+) m/z 452.2 (M+1).

EXAMPLE 16.36 Synthesis of1-cyclopentyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea

Following the procedure as described in EXAMPLE 16.35 and makingnon-critical variations using cyclopentylamine to replace n-hexylamine,1-cyclopentyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)ureawas obtained (61%) as a pale yellow solid: mp 133-135° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.73 (m, 1H), 7.31-7.25(m, 1H), 6.63-6.60 (m, 1H), 6.52 (s, 1H), 6.34 (s, 1H), 6.07 (s, 1H),4.77 (ABq, 2H), 4.20-4.11 (m, 5H), 3.81-3.76 (m, 1H), 3.28 (s, 3H),1.94-1.80 (m, 2H), 1.70-1.54 (m, 4H), 1.35-1.28 (m, 2H); ¹³C NMR (75MHz, CDCl₃) δ 176.3, 154.3, 145.2, 142.9, 139.3, 135.9, 129.8, 118.9,118.3, 116.0, 112.3, 103.3, 99.2, 78.2, 64.5, 63.9, 57.1, 52.3, 33.6,33.4, 27.0, 23.5, 23.5; MS (ES+) m/z 436.2 (M+1).

EXAMPLE 16.37 Synthesis of1-cyclohexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea

Following the procedure as described in EXAMPLE 16.35 and makingnon-critical variations using cyclohexylamine to replace n-hexylamine,1-cyclohexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)ureawas obtained (57%) as a colorless solid: mp 175-177° C. (ethyl acetate);¹H NMR (300 MHz, CDCl₃) δ 7.72-7.69 (m, 1H), 7.30-7.24 (m, 1H),6.63-6.60 (m, 1H), 6.53 (s, 1H), 6.34 (s, 1H), 6.05 (s, 1H), 4.76 (ABq,2H), 4.20-4.12 (m, 5H), 3.41 (s, 1H), 3.28 (s, 3H), 1.90-1.82 (m, 2H),1.71-1.58 (m, 3H), 1.41-1.01 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ 176.3,154.2, 153.9, 145.1, 142.9, 139.3, 135.9, 129.8, 119.3, 118.4, 116.1,112.2, 103.3, 99.2, 78.3, 64.5, 63.8, 57.2, 49.2, 33.6, 33.5, 27.0,25.5, 24.7; MS (ES+) m/z 450.1 (M+1).

EXAMPLE 16.38 Synthesis ofN-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

To a stirred solution of1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylicacid (0.200 g, 0.566 mmol) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.114 g, 0.736 mmol) inN,N-dimethylformamide (20 mL) was added N,N-diisoproylethylamine (0.30mL, 1.72 mmol) and hydroxybenzotriazole (0.092 g, 0.68 mmol). Thereaction mixture was stirred at ambient temperature for 10 min andcyclohexylamine (0.10 mL, 0.87 mmol) was added. The reaction mixture wasstirred at ambient temperature for 40 h and concentrated in vacuo toremove most of the N,N-dimethylformamide. The mixture was diluted withethyl acetate (150 mL), washed with water (3×150 mL) and brine (3×100mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography and eluted withethyl acetate/hexanes (1/1) to affordN-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.127 g, 51%) as a colorless solid: mp 139-140° C.; ¹H NMR (300 MHz,CDCl₃) δ7.42-7.36 (m, 1H), 7.24-7.20 (m, 1H), 6.98-6.94 (m, 1H), 6.51(s, 1H), 6.17 (s, 1H), 5.30-5.27 (m, 1H), 4.95 (ABq, 2H), 4.24-4.04 (m,4H), 3.71-3.61 (m, 1H), 3.26 (s, 3H), 1.78-1.57 (m, 5H), 1.36-1.22 (m,2H), 1.12-0.99 (m, 1H), 0.89-0.82 (m, 2H); ¹³C NMR (75 MHz, CDCl₃)δ177.6, 166.3, 155.9, 145.0, 144.3, 137.9. 134.7, 129.5, 127.4, 122.8,120.4, 110.7, 109.9, 100.1. 78.0, 64.5, 64.0, 58.2, 48.7, 32.4, 32.1,26.7, 25.5, 24.9, 24.7; MS (ES+) m/z 435.0 (M+1).

EXAMPLE 16.39 Synthesis ofN-cyclopentyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using cyclopentylamine to replacecyclohexylamine,N-cyclopentyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (28%) as a colorless solid: mp 135-136° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.36 (m, 1H), 7.24-7.22(m, 1H), 6.98-6.95 (m, 1H), 6.50 (s, 1H), 6.17 (s, 1H), 5.38-5.36 (m,1H), 4.95 (ABq, 2H), 4.20-4.06 (m, 5H), 3.26 (s, 1H), 1.92-1.78 (m, 2H),1.52-1.49 (m, 4H), 1.13-0.93 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6,166.8, 155.9, 145.0, 144.3, 137.9, 134.6, 129.5, 127.3, 122.8, 120.5,110.7, 109.9, 100.0, 78.9, 64.5, 64.0, 58.1, 51.5, 32.6, 32.4, 26.9,23.9, 23.7; MS (ES+) m/z 421.1 (M+1).

EXAMPLE 16.40 Synthesis ofN-cyclopropyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using cyclopropylamine to replacecyclohexylamine,N-cyclopropyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (36%) as a colorless solid: mp 127-128° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.36 (m, 1H), 7.24-7.22(m, 1H), 6.98-6.96 (m, 1H), 6.52 (s, 1H), 6.17 (s, 1H), 5.41 (s, 1H),4.90 (m, 2H), 4.21-4.11 (m, 4H), 3.26 (s, 3H), 2.67-2.60 (m, 1H),0.68-0.63 (m, 2H), 0.18-0.17 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5,168.5, 155.7, 145.1, 144.1, 137.9, 134.1, 129.6, 127.4, 122.9, 120.5,110.6, 110.0, 100.1, 78.7, 64.6, 64.0, 58.0, 26.9, 22.8, 6.4, 6.2; MS(ES+) m/z 415.0 (M+23).

EXAMPLE 16.41 Synthesis of1′-methyl-4′-(pyrrolidin-1-ylcarbonyl)-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using pyrrolidine to replace cyclohexylamine,1′-methyl-4′-(pyrrolidin-1-ylcarbonyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (8%) as a colorless solid: mp 242-244° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.36-7.30 (m, 1H), 6.92-6.89(m, 2H), 6.45 (s, 1H), 6.21 (s, 1H), 5.01 (ABq, 2H), 4.22-4.01 (m, 4H),3.49-3.40 (m, 1H), 3.29 (s, 3H), 3.21-3.11 (m, 1H), 3.02-2.93 (m, 1H),2.43-2.35 (m, 1H), 1.77-1.62 (m, 3H), 1.39-1.29 (m, 1H); ¹³C NMR (75MHz, CDCl₃) δ 177.6, 166.7, 156.2, 144.6, 143.4, 137.5, 135.4, 129.1,128.4, 120.4, 119.8, 111.1, 108.6, 99.0, 79.5, 64.6, 64.0, 58.2, 48.0,44.9, 26.9, 25.5, 24.4; MS (ES+) m/z 407.0 (M+1).

EXAMPLE 16.42 Synthesis of1′-methyl-2′-oxo-N-pentyl-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using n-pentylamine to replace cyclohexylamine,1-methyl-2′-oxo-N-pentyl-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (29%) as a pale yellow solid: mp 191-193° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.36 (m, 1H), 7.24-7.22(m, 1H), 6.99-6.95 (m, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 5.32-5.25 (m,1H), 4.92 (ABq, 2H), 4.21-4.09 (m, 4H), 3.30-3.17 (m, 1H), 3.27 (s, 3H),3.06-2.95 (m, 1H), 1.30-1.11 (m, 6H), 0.87 (t, J=7.1 Hz, 3H); 130 NMR(75 MHz, CDCl₃) δ 177.6, 167.0, 155.8, 145.0, 144.1, 137.9, 134.4,129.5, 127.8, 122.9, 120.6, 110.7, 109.9, 99.8, 78.8, 64.5, 64.0, 58.1,39.9, 29.0, 28.7, 26.9, 22.3, 13.9; MS (ES+) m/z 423.1 (M+1).

EXAMPLE 16.43 Synthesis ofN-(2-methoxyethyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using 2-methoxyethylamine to replacecyclohexylamine,N-(2-methoxyethyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (14%) as a colorless solid: mp 97-100° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.36 (m, 1H), 7.21-7.18(m, 1H), 6.99-6.96 (m, 1H), 6.45 (s, 1H), 6.18 (s, 1H), 5.75-5.69 (m,1H), 4.95 (ABq, 2H), 4.19-4.10 (m, 4H), 3.48-3.15 (m, 10H); ¹³C NMR (75MHz, CDCl₃) δ 177.8, 167.2, 155.9, 144.8, 144.1, 137.8, 134.0, 129.4,128.4, 122.4, 120.4, 110.8, 110.0, 99.4, 79.0, 70.9, 64.5, 63.9, 58.6,58.3, 39.4, 26.9; MS (ES+) m/z 411.0 (M+1).

EXAMPLE 16.44 Synthesis ofN-(4-fluorobenzyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.38 and makingnon-critical variations using 4-fluorobenzylamine to replacecyclohexylamine,N-(4-fluorobenzyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (13%) as a colorless solid: mp 149-150° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.38 (m, 1H), 7.30-7.27(m, 1H), 7.08-6.93 (m, 5H), 6.43 (s, 1H), 6.14 (s, 1H), 5.56-5.53 (m,1H), 4.96 (ABq, 2H), 4.53-4.46 (m, 1H), 4.20-3.93 (m, 5H), 3.27 (s, 1H);¹³C NMR (75 MHz, CDCl₃) δ 177.5, 166.9, 163.8, 155.7, 144.9, 144.2,137.9, 133.7, 133.3, 129.9, 129.8-129.6, 128.2, 123.0, 120.3, 115.6,115.3, 110.6, 110.3, 99.7, 78.9, 64.4, 63.8, 58.2, 43.4, 26.9; MS (ES+)m/z 461.0 (M+1).

EXAMPLE 16.45 Synthesis ofN-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

To a stirred solution of1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylicacid (0.200 g, 0.566 mmol) in N,N-dimethylformamide (12 mL) were addedhydroxybenzotriazole (0.151 g, 1.13 mmol),0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.364 g, 1.13 mmol) and N,N-diisopropylethylamine (0.81 mL, 4.5 mmol).The reaction mixture was stirred at ambient temperature for 15 min andN-hexylamine (0.15 mL, 1.1 mmol) was added. The reaction mixture stirredfor 72 h at ambient temperature and concentrated in vacuo. The residuewas dissolved in ethyl acetate and was washed with water (3×150 mL), 1 Maqueous sodium hydroxide (2×100 mL) and brine (2×100 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was recrystallized from hexanes/ethyl acetate to affordN-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.180 g, 73%) as a colorless solid: mp 172-173° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.36 (m 1H), 7.26-7.22(m, 1H), 6.99-6.96 (m, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 5.30-5.26 (m,1H), 4.92 (ABq, 2H), 4.25-4.07 (m, 4H), 3.27-2.97 (m, 5H), 1.30-1.18 (m,8H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 167.0,155.8, 145.0, 144.1, 137.9, 134.4, 129.5, 127.8, 122.9, 120.6, 110.7,109.9, 99.8, 78.8, 64.5, 64.0, 58.1, 40.0, 31.4, 28.9, 26.9, 26.5, 22.5,14.0; MS (ES+) m/z 437.1 (M+1).

EXAMPLE 16.46 Synthesis of1′-methyl-2′-oxo-N-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.45 and makingnon-critical variations using 2-(aminomethyl)pyridine to replacen-hexylamine,1′-methyl-2′-oxo-N-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (38%) as a colorless solid: mp 214-215° C. (ethyl acetate);¹H NMR (300 MHz, CDCl₃) δ 8.46-8.44 (m, 1H), 7.70-7.64 (m, 1H),7.43-7.37 (m, 1H), 7.26-7.14 (m, 3H), 7.00-6.97 (m, 1H), 6.62 (s, 1H),6.30 (s, 1H), 6.16 (s, 1H), 4.97 (ABq, 2H), 4.66-4.31 (m, 2H), 4.11-3.90(m, 4H), 3.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.8, 167.2, 155.8,155.7, 148.5, 144.5, 144.1, 137.7, 137.1, 133.9, 129.4, 128.9, 122.4,122.3, 122.2, 120.4, 110.8, 110.0, 99.2, 79.1, 64.3, 63.7, 58.4, 44.7,26.9; MS (ES+) m/z 444.1 (M+1).

EXAMPLE 16.47 Synthesis ofN-(4-fluorophenyl)-1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Following the procedure described in EXAMPLE 16.45 and makingnon-critical variations using 4-fluoroaniline to replace n-hexylamine,N-(4-fluorophenyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamidewas obtained (59%) as a pale pink solid: mp>250° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, DMSO-d₆) δ 10.00 (br s, 1H),7.52-7.47 (m, 1H), 7.39-7.34 (m, 2H), 7.26-7.20 (m, 2H), 7.12-7.06 (m,2H), 6.21 (s, 1H), 6.13 (s, 1H), 4.85 (ABq, 2H), 4.13-3.91 (m, 4H), 3.21(s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.6, 165.7, 158.7 (d,J_(C-F)=238.5 Hz), 156.1, 144.7, 144.2, 137.5, 135.4, 135.3, 134.5,129.5, 128.8, 122.5, 122.4, 121.6, 120.1, 115.4 (d, J_(C-F)=21.8 Hz),111.7, 110.8, 98.5, 79.8, 64.6, 64.0, 58.3, 27.1; MS (ES+) m/z 447.2(M+1).

EXAMPLE 16.48 Synthesis of4′-amino-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure described in EXAMPLE 16.19 and makingnon-critical variations using4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,4′-amino-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (79%) as an orange solid: ¹H NMR (300 MHz, CDCl₃) δ7.11-7.05 (m, 1H), 6.48 (s, 1H), 6.36-6.32 (m, 3H), 4.78 (s, 2H),4.21-4.11 (m, 4H), 3.84-3.58 (m, 2H), 1.76-1.66 (m, 2H), 1.39-1.33, (m,4H), 0.91 (t, J=6.6 Hz, 3H); MS (ES+) m/z 380.9 (M+1).

EXAMPLE 16.49 Synthesis of4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

4′-Bromo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.700 g, 1.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.14 g,0.16 mmol), sodium tert-butoxide (0.252 g, 2.62 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.29 g, 0.47 mmol) andbenzylamine (0.22 mL, 2.0 mmol) were combined in anhydrous toluene (20mL) and heated at 105° C. for 60 h. The reaction mixture was filteredthrough a pad of diatomaceous earth and the pad was washed with ethylacetate (150 mL). The filtrate was washed with saturated aqueous sodiumbicarbonate (100 mL), water (100 mL) and brine (100 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography and eluted with a 0% to25% gradient of ethyl acetate in dichloromethane to afford4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.227 g, 31%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d,J=4.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.34-7.17 (m, 5H), 7.02 (d, J=7.7Hz, 1H), 6.95 (dd, J=8.3, 8.3 Hz, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 6.15(ABq, 2H), 5.23 (ABq, 2H), 4.86 (ABq, 2H), 4.20-4.15 (m, 4H).

EXAMPLE 16.50 Synthesis of4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.251 g, 0.45 mmol) and palladium hydroxide on carbon (0.251 g, 20 drywt %, contains −50% water, 0.18 mmol), methanol (20 mL), glacial aceticacid (1 drop, catalytic amount) was placed under an atmosphere ofhydrogen (1 atm) and stirred at ambient temperature for 16 h. Further,palladium hydroxide on carbon (0.100 g, 20 dry wt %, contains −50%water, 0.072 mmol) and acetic acid (1 drop, catalytic amount) wereadded, the reaction mixture was again placed under an atmosphere ofhydrogen (1 atm) and allowed to react at ambient temperature for 72 h.The reaction mixture was filtered through a pad of diatomaceous earthand the pad was washed with ethyl acetate (50 mL). The filtrate waswashed with water (100 mL) and brine (100 mL). The organic phase wasdried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography and eluted with a 0% to25% gradient of ethyl acetate in dichloromethane, to yield4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.070 g, 33%) as a colorless solid: mp 243-245° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (d, J=4.6 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.58 (dd,J=7.7 Hz, J=5.0 Hz, 1H), 6.91 (dd, J=8.0 Hz, J=8.0 Hz, 1H), 6.54 (d,J=12.1 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 5.14(ABq, 2H), 4.71 (ABq, 2H), 4.52 (s, 2H), 4.17 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 178.0, 154.9, 152.6, 152.4, 144.7, 142.9, 142.8, 138.8, 134.2,134.1, 129.4, 122.0, 118.6, 114.5, 112.8, 111.3, 99.0, 77.2, 64.5, 63.9,57.2, 42.4; MS (ES+) m/z 469.9 (M+1).

EXAMPLE 16.51 Synthesis of4′-hydroxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]

To a solution of4′-bromo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole](0.30 g, 0.80 mmol) in anhydrous tetrahydrofuran (20 mL) at −98° C. wasadded tert-butyllithium (1.90 mL, 1.7 M solution in pentane, 3.2 mmol)and stirred for 15 min. Trimethyl borate (0.36 mL, 3.2 mmol) was addedand the reaction mixture was allowed to warm to ambient temperature andstirred for 16 h. A solution of hydrogen peroxide in water (0.28 mL, 35%w/w, 3.2 mmol) was added to the reaction mixture at 0° C., and themixture was allowed to warm to ambient temperature, stirred for 0.5 hand concentrated in vacuo. The residue was triturated with water andfiltered. The resultant solid was purified by column chromatography andeluted with a 0% to 50% gradient of ethyl acetate in dichloromethane toafford4′-hydroxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.004 g, 2%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 10.37 (s, 1H), 9.50 (s, 1H), 7.00 (dd, J=8.0, 8.0 Hz, 1H),6.39-6.34 (m, 3H), 6.08 (s, 1H), 4.64 (ABq, 2H), 4.09 (m, 4H); ¹³C NMR(75 MHz, DMSO-d₆) δ 179.3, 155.5, 154.1, 144.0, 143.6, 137.7, 130.1,121.0, 116.1, 111.1, 110.5, 101.8, 98.7, 76.8, 64.6, 64.0, 57.2; MS(ES+) m/z 311.7 (M+1).

EXAMPLE 16.52 Synthesis of4′-hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.51 and makingnon-critical variations using4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol],4′-hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(17-1)-onewas obtained (37%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 9.61 (s, 1H), 7.14 (dd, J=8.0, 8.0 Hz, 1H), 6.56 (d, J=7.7Hz, 1H), 6.50 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 6.12 (s, 1H), 4.67 (ABq,2H), 4.17-4.09 (m, 4H), 3.12 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.0,155.0, 153.3, 144.7, 143.6, 137.1, 129.6, 120.2, 114.6, 110.9, 110.8,100.2, 98.1, 76.2, 64.1, 63.5, 56.3, 26.5; MS (ES+) m/z 325.8 (M+1).

EXAMPLE 16.53 Synthesis of1′-methyl-4′-(pyridin-2-yloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

4′-Hydroxy-t-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.120 g, 0.37 mmol), copper(I) iodide (0.007 g, 0.04 mmol), potassiumcarbonate (0.066 g, 0.48 mmol), 2-bromopyridine (0.070 mL, 0.74 mmol),and 1-butyl-1H-imidazole (0.024 mL, 0.18 mmol) were combined inanhydrous toluene (1 mL) and heated in a sealed tube at 120° C. for 50h. Dichloromethane (25 mL) was added and the mixture was washed withwater (3×25 mL). The organic phase was dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was triturated inmethanol to afford1′-methyl-4′-(pyridin-2-yloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.080 g, 54%) as a colorless solid: mp 219-221° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.91-7.89 (m, 1H), 7.67-7.62 (m, 1H), 7.35 (dd, J=8.1, 8.1Hz, 1H), 6.98-6.94 (m, 2H), 6.72 (d, J=8.3 Hz, 1H), 6.65 (d, J=8.3 Hz,1H), 6.11 (d, J=10.4 Hz, 1H), 4.57 (ABq, 2H), 4.10-3.93 (m, 4H), 3.18(s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 162.4, 154.6, 149.4, 146.6,144.7, 143.7, 139.5, 137.1, 129.8, 123.0, 118.9, 118.5, 117.3, 111.5,110.6, 105.7, 97.9, 77.6, 64.0, 63.4, 56.5, 26.8; MS (ES+) m/z 403.2(M+1).

EXAMPLE 16.54 Synthesis of4′-[2-(2-methoxyethoxy)ethoxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.53 and makingnon-critical variations using 1-bromo-2-(2-methoxyethoxy)ethane toreplace 2-bromopyridine,4′-[2-(2-methoxyethoxy)ethoxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1'H)-onewas obtained (26%) as a colorless solid: mp 109-110° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.30 (dd, J=8.1, 8.1 Hz, 1H), 6.73 (dd, J=8.1, 5.6 Hz,1H), 6.39 (s, 1H), 6.12 (s, 1H), 4.69 (ABq, 2H), 4.17-4.07 (m, 4H),4.01-3.91 (m, 2H), 3.49 (t, J=4.5 Hz, 2H), 3.38-3.31 (m, 4H), 3.20 (s,3H), 3.15 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.0, 155.1, 154.3,144.4, 143.6, 137.0, 130.1, 120.0, 116.7, 110.7, 107.4, 102.1, 98.0,76.5, 71.2, 69.7, 68.7, 68.0, 64.1, 63.5, 57.9, 56.5, 26.5; MS (ES+) m/z428.1 (M+1).

EXAMPLE 16.55 Synthesis of1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.53 and makingnon-critical variations using 2-bromo-3-(trifluoromethyl)pyridine toreplace 2-bromopyridine,1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 8.11-8.06 (m, 2H), 7.42 (dd, J=8.0, 8.0 Hz, 1H), 7.17 (dd,J=7.5, 5.0 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.07(s, 1H), 6.04 (s, 1H), 4.61 (ABq, 2H), 4.11-3.93 (m, 4H), 3.21 (s, 3H);¹³C NMR (75 MHz, DMSO-d₆) δ 176.7, 159.0, 155.2, 151.1, 148.7, 145.6,144.1, 137.8 (m), 137.4, 130.6, 125.0, 123.3, 118.8, 117.9, 112.3,112.1, 111.6, 107.0, 98.2, 78.1, 64.5, 63.9, 57.0, 27.3; MS (ES+) m/z470.9 (M+1).

EXAMPLE 16.56 Synthesis of1′-methyl-4′-[4-(trifluoromethyl)phenoxy]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.53 and makingnon-critical variations using 1-bromo-4-(trifluoromethyl)benzene toreplace 2-bromopyridine,1′-methyl-4′-[4-(trifluoromethyl)phenoxy]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (36%) as a colorless solid: mp 198-201° C.; ¹H NMR (300MHz, DMSO-d₆) δ 7.52 (d, J=8.7 Hz, 2H), 7.44 (dd, J=8.1, 8.1 Hz, 1H),7.06 (d, J=7.8 Hz, 1H), 6.74 (dd, J=8.3, 1.9 Hz, 3H), 6.19 (s, 1H), 6.10(s, 1H), 4.66 (ABq, 2H), 4.12-3.93 (m, 4H), 3.23 (s, 3H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.2, 154.6, 149.8, 145.1, 143.8, 137.2, 130.6, 126.6(m), 123.1, 122.8, 122.4, 118.8, 116.2, 115.4, 111.1, 106.2, 98.0, 77.6,64.0, 63.3, 56.4, 26.8; MS (ES+) m/z 470.1 (M+1).

EXAMPLE 16.57 Synthesis of4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

4′-Hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.25 g, 0.77 mmol), benzyl bromide (0.13 mL, 1.1 mmol), and cesiumcarbonate (0.751 g, 2.30 mmol) were combined in anhydrousN,N-dimethylformamide (10 mL) at ambient temperature and stirred for 16h. The reaction mixture was concentrated in vacuo and the residue wastaken up in water (25 mL) and extracted with dichloromethane (3×25 mL).The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyand eluted with a 0% to 10% gradient of ethyl acetate indichloromethane, followed by recrystallization frommethanol/dichloromethane to afford4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.130 g, 41%) as a colorless solid: mp 198-200° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 7.32-7.23 (m, 4H), 7.03-7.01 (m, 2H), 6.81 (d, J=8.5 Hz, 1H)6.74 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.20 (s, 1H), 5.06 (s, 2H), 4.70(ABq, 2H), 4.19-4.11 (m, 4H), 3.16 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.4, 155.8, 154.4, 145.0, 144.3, 137.8, 137.3, 130.6, 128.5, 127.9,127.0, 120.5, 117.6, 111.5, 108.1, 102.8, 98.8, 77.5, 69.1, 64.7, 64.1,57.7, 27.1; MS (ES+) m/z 416.0 (M+1).

EXAMPLE 16.58 Synthesis of1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.57 and makingnon-critical variations using2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replacebenzyl bromide,1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp 157-159° C.; ¹H NMR (300MHz, DMSO-d₆) δ 8.77 (d, J=4.7 Hz, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.61(dd, J=8.0, 4.9 Hz, 1H), 7.31 (dd, J=8.1, 8.1 Hz, 1H), 6.83 (d, J=8.5Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.06 (s, 1H), 6.01 (s, 1H), 5.16 (ABq,2H), 4.59 (ABq, 2H), 4.14-4.06 (m, 4H), 3.14 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.4, 155.5, 154.8, 153.2, 153.0, 137.5, 135.3, 130.6,125.8, 124.6, 124.2, 124.1, 122.2, 120.1, 117.6, 111.2, 107.9, 103.0,98.0, 77.1, 69.2, 64.6, 64.0, 57.0, 27.1; MS (ES+) m/z 484.8 (M+1).

EXAMPLE 16.59 Synthesis of4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 2-(dimethylamino)pyridine-5-boronic acidto replace quinolin-3-ylboronic acid, and4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-onewas obtained (44%) as a colorless solid: mp 187-188° C.(methanol/dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 8.61-8.56 (m, 1H),7.80-7.77 (m, 1H), 7.70-7.62 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.81 (m,2H), 6.66 (dd, J=8.8, 2.5 Hz, 1H), 6.40 (s, 1H), 6.27 (s, 1H), 6.21 (d,J=8.8 Hz, 1H), 5.25 (d, J=15.8 Hz, 1H), 4.93 (d, J=15.8 Hz, 1H), 4.71(d, J=9.0 Hz, 1H), 4.46 (d, J=9.0 Hz, 1H), 4.30-4.08 (m, 4H), 3.05 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 158.5, 155.6, 155.4, 149.5, 147.4,144.7, 142.7, 138.0, 137.6, 137.2, 137.1, 129.5, 128.8, 125.9, 122.8,122.7, 122.0, 121.7, 111.2, 108.6, 104.3, 99.4, 64.6, 64.0, 58.4, 46.2,38.1; MS (ES+) m/z 507.0 (M+1).

EXAMPLE 16.60 Synthesis of4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 4-methoxyphenyl boronic acid to replacequinolin-3-ylboronic acid, and4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-onewas obtained (68%) as a colorless solid: mp 205-206° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

8.59 (d, J=4.7 Hz, 1H), 7.65-7.68 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.84(m, 2H), 6.78-6.61 (m, 4H), 6.41 (s, 1H), 6.25 (s, 1H), 5.26 (d, J=15.8Hz, 1H), 4.92 (d, J=15.8 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.36 (d, J=9.0Hz, 1H), 4.27-4.08 (m, 4H), 3.77 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ178.3, 158.9, 155.6, 155.5, 149.5, 144.6, 142.6, 140.0, 137.9, 137.1,130.9, 129.8, 129.0, 128.7, 125.7, 122.9, 122.8, 121.7, 113.2, 111.1,108.5, 99.4, 64.6, 64.0, 58.5, 55.3, 46.2; MS (ES+) m/z 493.0 (M+1).

EXAMPLE 16.61 Synthesis of(7S)-4′-furan-3-yl-1′-methylspiro[furo[2,3-d][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(950 mg, 2.63 mmol) was resolved on a semi-preparative chiral column(CHIRALPAK-IA, Chiral Technologies, Inc.) eluted with 2% acetonitrile intert-butylmethylether at 30 mL/min (25 min run time). Each run consistedof 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether(1:1).(7S)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas the first enantiomer to elute. Recrystallization fromdichloromethane and diethyl ether afforded(7S)-4′-furan-3-yl-t-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.38 g, 79%) as a colorless solid: mp 144-145° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃)

7.38-7.30 (m, 2H), 7.00 (dd, J=7.9, 0.9 Hz, 1H), 6.89-6.81 (m, 1H), 6.42(s, 1H), 6.21 (s, 1H), 6.05-6.03 (m, 1H), 5.89 (d, J=1.3 Hz, 1H), 5.85(d, J=1.3 Hz, 1H), 4.72 (d, J=9.1 Hz, 1H), 4.57 (d, J=9.1 Hz, 1H), 3.27(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1, 156.2, 149.1, 144.2, 142.8,142.0, 140.4, 131.0, 129.1, 128.2, 125.4, 122.5, 120.8, 111.1, 107.5,102.8, 101.6, 93.9, 58.5, 26.9; MS (ES+) m/z 361.9 (M+1).

EXAMPLE 16.62 Synthesis of(7R)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(950 mg, 2.63 mmol) was resolved on a semi-preparative chiral column(CHIRALPAK-IA, Chiral Technologies, Inc.) and eluted with 2%acetonitrile in tert-butylmethylether at 30 mL/min (25 min run time).Each run consisted of 50 mg of the racemate dissolved inacetonitrile/tert-butylmethylether (1:1).(7R)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-onewas the second enantiomer to elute. Recrystallization fromdichloromethane and diethyl ether afforded(7R)-4′-furan-3-yl-t-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.39 g, 82%) as a colorless solid: mp 144-145° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃)

7.38-7.30 (m, 2H), 7.00 (dd, J=7.9, 0.6 Hz, 1H), 6.89-6.81 (m, 1H), 6.42(s, 1H), 6.21 (s, 1H), 6.05-6.03 (m, 1H), 5.89 (d, J=1.2 Hz, 1H), 5.85(d, J=1.2 Hz, 1H), 4.72 (d, J=9.1 Hz, 1H), 4.57 (d, J=9.1 Hz, 1H), 3.27(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.1, 156.2, 149.1, 144.2, 142.8,142.0, 140.4, 131.0, 129.1, 128.2, 125.4, 122.5, 120.8, 111.1, 107.5,102.8, 101.6, 93.9, 58.5, 26.9; MS (ES+) m/z 361.9 (M+1).

EXAMPLE 16.63 Synthesis of(7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column(CHIRALPAK-IA, Chiral Technologies, Inc.) eluted with 5% acetonitrile intert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of theracemate dissolved in acetonitrile/tert-butylmethylether (1:1).(7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.14 g, 86%) was the first enantiomer to elute and was obtained as acrystalline colorless solid:. mp 226-228° C.(acetonitrile/tert-butylmethylether); ¹H NMR (300 MHz, DMSO-d₆) δ7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H),6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).

EXAMPLE 16.64 Synthesis of(7S)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.32 g, 8.58 mmol) was resolved on a semi-preparative chiral column(CHIRALPAK-IA, Chiral Technologies, Inc.) and eluted with 5%acetonitrile in tent-butylmethylether at 30 mL/min. Each run consistedof 50 mg of the racemate dissolved in acetonitrile/tert-butylmethylether(1:1).(7S)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.13 g, 81%) was the second enantiomer to elute and was isolated as acrystalline colorless solid: mp 226-227° C.(acetonitrile/tert-butylmethylether); ¹H NMR (300 MHz, DMSO-d₆)

7.31-7.23 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 1H), 6.59 (s, 1H),6.28 (s, 1H), 5.92-5.87 (m, 2H), 4.82 (d, J=9.7 Hz, 1H), 4.67 (d, J=9.7Hz, 1H), 3.15 (s, 3H); MS (ES+) m/z 373.8, 375.8 (M+1).

EXAMPLE 16.65 Synthesis of(7S)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.25 g) was resolved on a semi-preparative chiral column (CHIRALPAK-IA,Chiral Technologies, Inc.) and eluted with 5% acetonitrile intert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of theracemate dissolved first in dimethylsulfoxide (0.15 mL) and diluted withacetonitrile (0.85 mL) and tert-butylmethylether (1.00 mL). The productwas dissolved in dimethylsulfoxide (2.0 mL), precipitated with water(50.0 mL), filtered and air dried to afford(7S)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.11 g, 88%) as a colorless solid. This enantiomer was the first toelute. mp 230-231° C. (water); ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s,1H), 7.57 (dd, J=1.6, 1.6 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.03(s, 1H), 6.90 (dd, J=7.1, 7.1 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 6.06(d, J=0.8 Hz, 1H), 5.92 (d, J=4.8 Hz, 2H), 4.60 (d, J=9.4 Hz, 1H), 4.44(d, J=9.4 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 179.2, 156.1, 148.8,143.8, 143.3, 142.0, 140.5, 130.5, 129.6, 128.9, 124.3, 123.2, 121.4,111.3, 109.7, 103.3, 101.9, 93.7, 77.6, 58.6; MS (ES+) m/z 347.9 (M+1).

EXAMPLE 16.66 Synthesis of(7R)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

4′-Furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.25 g) was resolved on a semi-preparative chiral column (CHIRALPAK-IA,Chiral Technologies, Inc.) and eluted with 5% acetonitrile intert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of theracemate dissolved first in dimethylsulfoxide (0.15 mL) and diluted withacetonitrile (0.85 mL) and tert-butylmethylether (1.00 mL). The productisolated was dissolved in dimethylsulfoxide (2.0 mL), precipitated withwater (50.0 mL), filtered and air dried to afford(7R)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.10 g, 75%) as a colorless solid. This enantiomer was the second toelute: mp 229-231° C. (water); ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s,1H), 7.57 (dd, J=1.6, 1.6 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.03(s, 1H), 6.90 (dd, J=7.1, 7.1 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 6.06(d, J=0.8 Hz, 1H), 5.92 (d, J=4.8 Hz, 2H), 4.60 (d, J=9.4 Hz, 1H), 4.44(d, J=9.4 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 179.2, 156.1, 148.8,143.8, 143.3, 142.0, 140.5, 130.5, 129.6, 128.9, 124.3, 123.2, 121.4,111.3, 109.7, 103.3, 101.9, 93.7, 77.6, 58.6; MS (ES+) m/z 347.9 (M+1).

EXAMPLE 16.67 Synthesis of1′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 1H-pyrazol-3-boronic acid to replacequinolin-3-ylboronic acid, and4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (63%) as a colorless solid: mp 201-202° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.46-7.35 (m,2H), 7.25-7.20 (m, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.40 (s, 1H), 6.24 (s,1H), 5.94 (d, J=2.0 Hz, 1H), 4.74-4.61 (m, 2H), 4.20-4.07 (m, 4H), 3.27(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0, 155.6, 144.7, 144.5, 137.8,129.2, 128.0, 124.6, 121.6, 111.0, 108.2, 105.5, 99.5, 77.4, 64.5, 63.9,58.4, 26.9; MS (ES+) m/z 375.9 (M+1).

EXAMPLE 16.68 Synthesis of4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 3-furanboronic acid to replacequinolin-3-ylboronic acid, and4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,4′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (65%) as a colorless solid: mp 178-180° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.29 (m, 2H), 7.00 (d,J=7.9 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.41 (s, 1H), 6.28(s, 1H), 6.04-6.01 (m, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (d, J=9.0 Hz,1H), 4.23-4.09 (m, 4H), 3.26 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0,155.5, 144.7, 144.3, 142.8, 140.5, 137.9, 130.8, 129.1, 128.1, 125.2,122.6, 122.5, 111.2, 111.1, 107.4, 99.7, 76.7, 64.6, 64.0, 58.3, 26.8;MS (ES+) m/z 375.9 (M+1).

EXAMPLE 16.69 Synthesis of1′-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using 1H-pyrazole-4-boronic acid to replacequinolin-3-ylboronic acid, and4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (54%) as a colorless solid: mp 250-251° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.35 (dd, J=7.9, 7.9 Hz, 1H), 7.10-7.00 (m, 3H), 6.86 (d, J=7.8 Hz, 1H),6.40 (s, 1H), 6.31 (s, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.47 (d, J=9.1 Hz,1H), 4.23-4.08 (m, 4H), 3.26 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0,155.4, 144.8, 144.3, 138.0, 130.6, 129.2, 127.9, 125.4, 122.5, 111.4,107.3, 99.6, 64.6, 63.9, 58.2, 26.8; MS (ES+) m/z 376.0 (M+1).

EXAMPLE 16.70 Synthesis of1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 2.46 and makingnon-critical variations using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole toreplace quinolin-3-ylboronic acid, and4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (58%) as a colorless solid: mp 220-222° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃)

7.32 (dd, J=7.9, 7.9 Hz, 1H), 7.16 (s, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.83(d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 4.66 (d,J=9.1 Hz, 1H), 4.48 (d, J=9.1 Hz, 1H), 4.23-4.09 (m, 4H), 3.75 (s, 3H),3.25 (s, 3H); 130 NMR (75 MHz, CDCl₃) δ 178.0, 155.6, 144.8, 144.2,138.7, 138.0, 130.8, 129.3, 129.1, 127.8, 125.2, 122.7, 119.0, 111.5,107.0, 99.4, 76.7, 64.6, 64.0, 58.3, 38.9, 26.8; MS (ES+) m/z 390.0(M+1).

EXAMPLE 16.71 Synthesis of1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indole]-4′-carbonitrile

Following the procedure as described in EXAMPLE 2.48 and makingnon-critical variations using4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneto replace6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrilewas obtained (74%) as a colorless solid: mp 196-197° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.36 (m, 1H), 7.32-7.27(m, 1H), 7.11-7.07 (m, 1H), 6.52 (s, 1H), 6.14 (s, 1H), 4.94-4.83 (m,2H), 4.22-4.06 (m, 4H), 3.28 (s, 3H); MS (ES+) m/z 334.9 (M+1).

EXAMPLE 16.72 Synthesis of1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

To a suspension of1′-methyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile(0.25 g, 0.75 mmol) in ethanol (30 mL) was added saturated aqueoussodium carbonate (3 mL) and 30% w/w aqueous hydrogen peroxide (3 mL).The reaction mixture was heated at reflux for 3 h, allowed to cool toambient temperature and concentrated in vacuo. The residue wastriturated in water to afford1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.09 g, 33%) as a colorless solid: mp>250° C. (water); ¹H NMR (300 MHz,CDCl₃)

7.59 (s, 1H), 7.43-7.36 (m, 1H), 7.24-7.13 (m, 3H), 6.28 (s, 1H), 5.98(s, 1H), 5.15 (d, J=8.1 Hz, 1H), 4.57 (d, J=8.1 Hz, 1H), 4.16-3.99 (m,4H), 3.13 (s, 3H); MS (ES+) m/z 352.9 (M+1).

EXAMPLE 16.73 Synthesis of1′-methyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one

To a solution of4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.60 g, 1.66 mmol) in ethyl acetate (30 mL) was added palladium oncarbon (10% w/w, 0.40 g). The reaction mixture was shaken under apressure of hydrogen gas (60 psi) in a Parr hydrogenation apparatus atambient temperature for 16 h and filtered through a pad of diatomaceousearth. The filtrate was concentrated in vacuo and the residuerecrystallized from dichloromethane/diethyl ether to affordmethyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.44 g, 73%) as a colorless solid: mp 182-184° C.(dichloromethane/ether); ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.35 (m, 1H),7.08-7.01 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.52-6.48 (m, 1H), 6.15 (d,J=13.3 Hz, 1H), 5.90-5.84 (m, 2H), 4.96 (dd, J=9.26, 1.0 Hz, 1H),4.78-4.67 (m, 1H), 4.11-3.59 (m, 3H), 3.39-3.18 (m, 2H), 2.40-1.94 (m,1H), 1.63-1.36 (m, 1H); MS (ES+) m/z 365.9 (M+1).

EXAMPLE 16.74 Synthesis of1′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile(0.35 g, 1.05 mmol) in dimethylsulfoxide (10 mL) was added hydroxylamine(50% w/w solution in water, 3.0 mL). The reaction mixture was stirredfor 16 h at ambient temperature, poured into water (50 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith brine (2×50 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was triturated in hexanes to affordN′-hydroxy-1′-methyl-2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-4′-carboximidamide(0.37 g) as a colorless solid. To a 10 mL microwave reaction vessel wereaddedN′-hydroxy-1′-methyl-2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-4′-carboximidamide(0.20 g, 0.54 mmol), acetic anhydride (0.50 mL) and pyridine (2.00 mL).The solution was heated at 160° C. for 0.5 h in a microwave reactor,allowed to cool to ambient temperature and concentrated in vacuo. Theresidue was purified by column chromatography and eluted withhexanes/ethyl acetate (3/1) followed by recrystallization from diethylether to afford1-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.08 g, 37%) as a colorless solid: mp 199-201° C. (diethyl ether); ¹HNMR (300 MHz, CDCl₃) δ 7.70 (dd, J=8.0, 0.8 Hz, 1H), 7.46 (t, J=7.9 Hz,1H), 7.03 (dd, J=7.8, 0.8 Hz, 1H), 6.39 (s, 1H), 6.03 (s, 1H), 5.14 (d,J=8.6 Hz, 1H), 4.82 (d, J=8.6 Hz, 1H), 4.16-4.00 (m, 4H), 3.28 (s, 3H),2.50 (s, 3H); MS (ES+) m/z 391.9 (M+1).

EXAMPLE 16.75 Synthesis of4′-(3,5-dimethylisoxazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a 10 mL reaction vessel were added4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(0.50 g, 1.3 mmol), 3,5-dimethylisoxazole-4-boronic acid (0.37 g, 2.6mmol), palladium acetate (0.018 g, 0.026 mmol),dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.021 g, 0.052 mmol),potassium carbonate (0.54 g, 3.9 mmol), acetonitrile (2.0 mL) and water(1.5 mL). The vessel was heated for 16 h at 100° C. under microwaveirradiation, allowed to cool to ambient temperature, diluted with water(25 mL) and extracted with ethyl acetate (3×75 mL). The combined organicextracts were washed with brine (50 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with a 20% to 60% gradient of ethyl acetate inhexanes to afford4′-(3,5-dimethylisoxazol-4-yl)-t-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.422 g, 80%) as a colorless solid: mp 228-230° C. (ethylacetate/hexanes); ¹H NMR (mixture of atropisomers, 300 MHz, CDCl₃) δ7.39-7.29 (m, 1H), 6.95 (d, J=7.79 Hz, 1H), 6.73 (d, J=7.76 Hz, 1H),6.26 (s, 1H), 6.21 (d, J=7.14 Hz, 1H), 4.70 (dd, J=8.9, 3.4 Hz, 1H),4.39 (dd, J=17.4, 9.0 Hz, 1H), 4.17-4.03 (m, 4H), 3.31 (s, 1.5H), 3.30(s, 1.5H), 2.24 (s, 1.5H), 2.07 (s, 1.5H), 1.40 (s, 1.5H), 1.32 (s,1.5H); MS (ES+) m/z 405.0 (M+1).

EXAMPLE 16.76 Synthesis ofN,1′-dimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate(0.30 g, 0.70 mmol), methylamine hydrochloride (0.12 g, 1.8 mmol),potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0mL) were added to a microwave reaction vessel. The reaction was heatedat 100° C. for 0.5 h in a microwave reactor. Further, methylaminehydrochloride (0.20 g, 3.0 mmol) was added and the mixture was heated at100° C. for an additional 45 min in a microwave reactor. The mixtureallowed to cool to ambient temperature, poured into water (25 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine (2×50 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The product was precipitated fromdichloromethane with diethyl ether and subsequently recrystallized fromethyl acetate to afford N,t-dimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.08 g, 32%) as a colorless solid: mp 120-122° C. (ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 7.41-7.31 (m, 1H), 7.25-7.19 (m, 1H), 6.98-6.93(m, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 5.19 (d, J=3.2 Hz, 1H), 4.87 (s,2H), 4.21-4.08 (m, 4H), 3.26 (s, 3H), 2.64 (d, J=4.9 Hz, 3H); MS (ES+)m/z 366.9 (M+1).

EXAMPLE 16.77 and Example 16.78 Synthesis ofN-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indole]-4′-carboxamideandN,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide

Phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indole]-4′-carboxylate(0.30 g, 0.70 mmol), cyclobutylamine hydrochloride (0.23 g, 2.1 mmol),potassium carbonate (0.39 g, 2.8 mmol) and N,N-dimethylformamide (3.0mL) were added to a microwave reaction vessel. The reaction was heatedat 110° C. for 1 h in a microwave reactor, allowed to cool to ambienttemperature, poured into water (25 mL) and extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with 1 Mhydrochloric acid (50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 20% to 100% gradient of ethylacetate in hexanes followed by recrystallization fromdichloromethane/diethyl ether to affordN-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.045 g, 17%) as a colorless solid: mp 128-129° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.33 (m,1H), 7.26-7.21 (m, 1H), 6.97-6.93 (m, 1H), 6.51 (s, 1H), 6.20 (s, 1H),5.46 (d, J=6.65 Hz, 1H), 4.96-4.81 (m, 2H), 4.35-4.01 (m, 5H), 3.25 (s,3H), 2.27-2.09 (m, 2H), 1.70-1.40 (m, 4H); MS (ES+) m/z 407.0 (M+1).N,N,1′-trimethyl-2′-oxo-1,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide(0.12 g, 37%) was isolated as a byproduct from the synthesis ofN-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide,obtained as colorless solid: mp 218-221° C. (dichloromethane/diethylether); ¹H NMR (300 MHz, CDCl₃)

7.32 (dd, J=7.8, 7.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.44 (s, 1H), 6.22 (s,1H), 5.05 (d, J=8.8 Hz, 1H), 4.79 (d, J=8.8 Hz, 1H), 4.20-4.04 (m, 4H),3.28 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 381.0 (M+1).

EXAMPLE 16.79 Synthesis of4′-(3-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 10 mL sealed tube was charged with4′-bromo-t-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one(0.77 g, 2.0 mmol), 3-methoxyphenol (0.50 g, 4.0 mmol), potassiumcarbonate (0.36 g, 2.6 mmol), copper (I) iodide (0.038 g, 0.2 mmol),1-methylimidazole (0.082 g, 1.0 mmol) and anhydrous toluene (3 mL). Thereaction mixture was heated at 150° C. for 16 h, allowed to cool toambient temperature and filtered. The filtrate was concentrated in vacuoand the residue was purified by column chromatography and eluted with a15% to 50% gradient of ethyl acetate in hexanes to afford4′-(3-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.27 g, 31%) as an off-white solid: mp 166-168° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃ δ 7.20-7.27 (m, 1H), 7.02-7.10(m, 1H), 6.68 (d, J=7.7 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.50-6.58 (m,1H), 6.35-6.29 (m, 1H), 6.25 (s, 1H), 6.21 (t, J=2.0, Hz, 1H), 6.19 (s,1H), 4.83 (ABq, 2H), 4.15-4.01 (m, 4H), 3.69 (s, 3H), 3.27 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ177.5, 160.5, 157.7, 155.5, 152.7, 144.8, 144.3,137.7, 130.1, 129.7, 121.7, 119.2, 114.6, 111.0, 110.2, 109.0, 104.0,103.9, 99.0, 77.7, 64.4, 63.8, 57.3, 55.2, 27.0; MS (ES+) m/z 432.0(M+1).

EXAMPLE 16.80 Synthesis of1′-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.79 and makingnon-critical variations using phenol to replace 3-methoxyphenol,1′-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (49%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.35-7.11 (m, 3H), 6.93-7.04 (m, 1H), 6.76-6.63 (m, 3H), 6.54 (d, J=8.4Hz, 1H), 6.25 (s, 1H), 6.21 (s, 1H), 4.84 (ABq, 2H), 4.17-3.98 (m, 4H),3.27 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.5, 156.4, 155.5, 153.0,144.8, 144.3, 137.7, 130.1, 129.3, 123.2, 121.4, 119.3, 118.2, 114.1,111.0, 103.8, 99.0, 77.6, 64.4, 63.8, 57.4, 27.0; MS (ES+) m/z 402.0(M+1).

EXAMPLE 16.81 Synthesis of1′-methyl-4′-(3-morpholin-4-ylphenoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.79 and makingnon-critical variations using 3-morpholinophenol to replace3-methoxyphenol,1′-methyl-4′-(3-morpholin-4-ylphenoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (53%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ7.18-7.24 (m, 1H), 7.01-7.09 (m, 1H), 6.65 (d, J=7.7 Hz, 1H), 6.55 (d,J=8.5 Hz, 2H), 6.27 (s, 1H), 6.26-6.21 (m, 2H), 6.20 (s, 1H), 4.84 (ABq,2H), 4.13-4.00 (m, 4H), 3.82-3.74 (m, 4H), 3.25 (s, 3H), 3.07-3.00 (m,4H); ¹³C NMR (75 MHz, CDCl₃) δ177.6, 157.5, 155.6, 153.3, 152.5, 144.8,144.3, 137.6, 130.1, 129.7, 121.1, 119.4, 114.0, 111.0, 110.5, 109.7,105.9, 103.6, 99.1, 77.6, 66.7, 64.4, 63.8, 57.3, 48.9, 27.0; MS (ES+)m/z 486.9 (M+1).

EXAMPLE 16.82 Synthesis of4′-[(6-methoxypyridin-3-yl)oxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.79 and makingnon-critical variations using 6-methoxypyridin-3-ol to replace3-methoxyphenol, and 1-butylimidazole to replace 1-methylimidazole,4′-[(6-methoxypyridin-3-yl)oxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (33%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.64(s, 1H), 7.27-7.18 (m, 1H), 6.91-6.99m, 1H), 6.62-6.69 (m, 1H),6.54-6.58 (m, 1H), 6.42-6.48 (m, 1H), 6.27-6.30 (m, 1H), 6.18-6.22 (m,1H), 4.85 (ABq, 2H), 4.15-4.03 (m, 4H), 3.85 (s, 3H), 3.26 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 177.4, 160.2, 155.5, 153.6, 147.5, 144.9, 144.4,137.8, 136.9, 130.2, 130.1, 120.8, 119.2, 112.7, 111.0, 103.8, 99.1,77.7, 64.4, 63.8, 57.3, 53.6, 27.0; MS (ES+) m/z 432.9 (M+1).

EXAMPLE 16.83 Synthesis of4′-(1,3-benzodioxol-5-yloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.79 and makingnon-critical variations using benzo[d][1,3]dioxol-5-ol to replace3-methoxyphenol and 1-butylimidazole to replace 1-methylimidazole,4′-(1,3-benzodioxol-5-yloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (8%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.21(s, 1H), 6.67-6.57 (m, 2H), 6.50 (d, J=8.5 Hz, 1H), 6.32 (s, 1H),6.25-6.15 (m, 3H), 5.89 (s, 2H), 4.84 (ABq, 2H), 4.18-4.04 (m, 4H), 3.26(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.5, 155.6, 153.9, 150.9, 148.0,144.8, 144.3, 143.7, 137.7, 130.0, 120.6, 119.4, 113.1, 111.2, 111.0,107.8, 103.4, 101.5, 101.4, 99.0, 77.5, 64.4, 63.9, 57.3, 27.0; MS (ES+)m/z 445.8 (M+1).

EXAMPLE 16.84 Synthesis of4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 10 mL microwave reaction vessel was charged with4′-bromo-1′-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one(0.19 g, 0.5 mmol), 4-methoxyphenol (0.12 g, 1.0 mmol), potassiumtert-butoxide (0.11 g, 1.0 mmol), copper (I) bromide (0.012 g, 0.08mmol) and anhydrous 1-methylpyrrolidin-2-one (2 mL). The reactionmixture was irradiated at 250° C. for 75 min in a microwave reactor andwas allowed to cool to ambient temperature. The reaction mixture waspoured into water (15 mL) and extracted with ethyl acetate (50 mL). Thecombined organic extracts were washed with water (3×50 mL) and brine (50mL), dried over magnesium sulfate, filtered and concentrated in vacuo.Purification of the residue by column chromatography and eluted with a15% to 50% gradient of ethyl acetate in hexanes afforded4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.084 g, 39%) as an off-white solid: mp 55-58° C. (ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ7.27-7.14 (m, 1H), 6.78-6.59(m, 5H), 6.44 (d, J=8.48 Hz, 1H), 6.31 (d, J=1.08 Hz, 1H), 6.22 (d,J=1.08 Hz, 1H), 4.86 (ABq, 2H), 4.16-4.03 (m, 4H), 3.74 (s, 3H), 3.26(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 155.8, 155.6, 154.3, 149.6,144.8, 144.3, 137.7, 130.0, 120.2, 120.1, 119.5, 114.5, 112.7, 111.0,103.1, 99.1, 64.4, 63.9, 57.4, 55.6, 27.0; MS (ES+) m/z 432.0 (M+1).

EXAMPLE 16.85 Synthesis of1′-methyl-4-(pyridine-2-ylmethoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 25 mL flask was charged with4-hydroxy-1′-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one(0.33 g, 1.0 mmol), 2-(bromomethyl)pyridine hydrobromide (0.4 g, 1.6mmol), cesium carbonate (0.98 g, 3.0 mmol) and anhydrousN,N-dimethylformamide (6 mL). The reaction mixture was heated at 100° C.for 1.5 h and was allowed to cool to ambient temperature and filtered.The filtrate was concentrated in vacuo and the residue was purifiedcolumn chromatography and eluted with a 15% to 80% gradient of ethylacetate in hexanes to afford1′-methyl-4-(pyridine-2-ylmethoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.202 g, 49%) as an off-white solid: mp 181-183° C. (methanol); ¹H NMR(300 MHz, CDCl₃) δ 8.46 (d, J=4.7 Hz, 1H), 7.56-7.60 (m, 1H), 7.24-7.26(m, 1H), 7.17-7.10 (m, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.66 (d, J=8.5 Hz,1H), 6.57 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.25 (s, 1H), 5.14-5.01 (m,2H), 4.86 (ABq, 2H), 5.18-4.99 (m, 1H), 4.17-4.03 (m, 4H), 3.24 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 177.9, 156.7, 155.8, 154.3, 148.6, 144.5,144.3, 137.8, 136.8, 130.3, 122.4, 120.7, 119.8, 117.6, 111.4, 107.3,102.0, 98.9, 77.5, 70.1, 64.5, 63.9, 57.4, 26.9; MS (ES+) m/z 417.0(M+1).

EXAMPLE 16.86 Synthesis of1′-methyl-4-(4-fluorobenzyloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.85 and makingnon-critical variations using 1-(bromomethyl)-4-fluorobenzene to replace2-(bromomethyl)pyridine hydrobromide,t-methyl-4-(4-fluorobenzyloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (62%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ7.21-7.28 (m, 1H), 7.04-6.88 (m, 4H), 6.63 (d, J=8.5 Hz, 1H), 6.56 (d,J=7.8 Hz, 1H), 6.41 (s, 1H), 6.23 (s, 1H), 4.93 (ABq, 2H), 4.81 (ABq,2H), 4.21-4.05 (m, 4H), 3.23 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.9,163.8, 160.6, 155.9, 154.5, 144.6, 144.3, 137.7, 132.1, 132.0, 130.1,128.4, 128.3, 119.8, 117.9, 115.2, 115.0, 111.2, 107.5, 101.9, 99.0,77.5, 68.9, 64.5, 63.9, 57.4, 26.9; MS (ES+) m/z 434.2 (M+1).

EXAMPLE 16.87 Synthesis of4′-(4-fluorophenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.53 and makingnon-critical variations using 1-bromo-4-fluorobenzene to replace2-bromopyridine,4′-(4-fluorophenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (41%) as an off-white solid: mp 151-153° C. (methanol); ¹HNMR (300 MHz, CDCl₃) δ 7.21-7.27 (m, 1H), 6.80-6.88 (m, 2H), 6.71-6.60(m, 3H), 6.51 (d, J=8.4 Hz, 1H), 6.25 (s, 1H), 6.17 (s, 1H), 4.83 (ABq,2H), 4.14-4.01 (m, 4H), 3.26 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4,160.2, 157.0, 155.5, 153.1, 152.4, 152.4, 144.9, 144.3, 137.7, 130.2,121.5, 119.4, 119.3, 119.1, 115.9, 115.6, 113.9, 111.0, 104.0, 99.0,77.7, 64.4, 63.9, 57.3, 27.0; MS (ES+) m/z 420.0 (M+1).

EXAMPLE 16.88 Synthesis of1′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 16.12 and makingnon-critical variations using (6-methoxypyridin-3-yl)boronic acid toreplace 6-(dimethylamino)pyridin-3-ylboronic acid, and5-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneto replace4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,1′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onewas obtained (20%) as a colorless solid: mp 60-62° C.; ¹H NMR (300 MHz,CDCl₃)

8.16 (d, J=2.5 Hz, 1H), 7.54 (dd, J=8.6, 2.2 Hz, 1H), 7.35 (dd, J=8.4,1.6 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 7.07-6.98(m, 2H), 6.95 (d, J=7.8 Hz, 1H), 6.88 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 5.12 (d, J=15.8 Hz, 1H), 5.00 (d, J=9.2 Hz, 1H), 4.91 (d,J=15.8 Hz, 1H), 4.73 (d, J=9.2 Hz, 1H), 3.89 (s, 3H); ¹³C NMR (75 MHz,CDCl₃)

176.9, 163.2, 160.3, 144.5, 141.3, 137.2, 136.9, 132.2, 131.7, 130.1,129.8, 129.6, 129.1, 128.5, 126.4, 126.0, 124.1, 123.9, 121.7, 110.9,110.6, 109.0, 79.7, 60.4, 58.0, 53.5, 39.2; MS (ES+) 475.5 (M+1) 477.5(M+1).

EXAMPLE 17 Synthesis of1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one

A mixture of1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(2.4 g, 5.1 mmol) and palladium on carbon (10% w/w, 0.49 g) in anhydrousmethanol (10 mL) and ethyl acetate (50 mL) was hydrogenated at ambienttemperature under a balloon pressure for 16 h. The mixture was filteredthrough a pad of diatomaceous earth The pad was washed with ethylacetate (50 mL) and the filtrate was concentrated in vacuo. The residuewas purified by column chromatography and eluted with a 25% to 50%gradient of ethyl acetate in hexanes to afford1-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one(1.86 g, 94%) as a colorless solid: mp 226-227° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.25-7.13 (m, 4H), 7.06-6.99 (m, 1H), 6.87-6.82 (m, 1H),6.78-6.72 (m, 2H), 6.44-6.41 (m, 2H), 5.27 (s, 1H), 4.88 (ABq, J=69.0,15.3 Hz, 2H), 4.84 (ABq, J=82.9, 9.0 Hz, 2H), 4.55-4.46 (m, 2H),2.96-2.86 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.2, 161.8, 161.3, 155.5,142.1, 132.8, 128.8, 128.7, 127.5, 123.9, 123.5, 120.0, 119.9, 118.8,115.8, 109.4, 93.3, 80.5, 72.4, 70.0, 57.8, 43.7, 28.9; MS (ES+) m/z385.9 (M+1).

EXAMPLE 17.1 Synthesis of1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 17 and makingnon-critical variations using1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-[4(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (93%) as a colorless solid: mp 243-244° C.; ¹H NMR (300MHz, CDCl₃) δ 9.42 (s, 1H), 7.30-7.22 (m, 1H), 7.20-7.13 (m, 3H),7.05-6.97 (m, 2H), 6.76-6.68 (m, 2H), 6.52 (s, 1H), 6.04 (s, 1H),4.89-4.63 (m, 4H), 4.21-4.07 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 176.6,156.7, 154.6, 144.1, 142.1, 137.7, 131.7, 128.6, 126.4, 123.5, 122.9,121.2, 115.3, 110.8, 109.5, 98.8, 79.3, 64.1, 63.5, 57.1, 42.5; MS (ES+)m/z 401.9 (M+1).

EXAMPLE 17.2 Synthesis of1′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in Example 17 and makingnon-critical variations using1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-[4(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one,1-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (83%): mp 157-158° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 7.33-7.27 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.03 (m, 1H),6.95-6.92 (m, 1H), 6.48 (s, 1H), 6.19 (s 1H), 4.73 (ABq, 2H), 4.19-4.08(m, 4H), 3.02-3.80 (m, 2H), 3.61-3.55 (m, 2H), 2.98 (d, J=6.0 Hz, 1H),1.98-1.85 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 178.8, 155.3, 144.6, 141.9,138.3, 132.4, 128.9, 124.1, 123.6, 120.6, 111.4, 108.5, 99.4, 80.0,64.5, 63.9, 58.3, 58.1, 36.4, 29.8; MS (ES+) m/z 353.8 (M+1).

EXAMPLE 18 Synthesis of ethyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate

To a cooled (0° C.) suspension of sodium hydride (60% w/w in mineraloil, 0.16 g, 3.7 mmol) in anhydrous N,N-dimethylformamide (30 mL) wasadded2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.99 g, 3.39 mmol), followed by ethyl chloroformate (0.35 mL, 3.7mmol). The reaction mixture was stirred at ambient temperature for 18 hand was concentrated in vacuo. The residue was purified by columnchromatography and eluted with a 5% to 66% gradient of ethyl acetate inhexanes to afford ethyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate(0.68 g, 55%) as a colourless solid: mp 198-200° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.96 (d, J=7.7 Hz, 1H), 7.39-7.34 (m,1H), 7.19-7.18 (m, 2H), 6.50 (s, 1H), 6.27 (s, 1H), 4.93 (d, J=9.1 Hz,1H), 4.63 (d, J=9.1 Hz, 1H), 4.49 (q, J=7.1 Hz, 2H), 4.21-4.18 (m, 2H),4.13-4.10 (m, 2H) 1.45 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)δ175.7, 155.1, 150.8, 144.9, 138.7, 138.4, 130.7, 129.2, 125.5, 123.8,121.0, 115.2, 111.7, 99.4, 80.8, 64.5, 63.9, 63.7, 58.6, 14.2; MS (ES+)m/z 367.7 (M+1).

EXAMPLE 18.1 Synthesis of tert-butyl4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-1′(2′H)-carboxylate

A mixture of4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.99g, 2.8 mmol), di-tert-butyl dicarbonate (1.0 mL, 4.4 mmol) and sodiumhydroxide (0.28 g, 6.9 mmol) and tetrahydrofuran/water (5/2, 46 mL) wasstirred at ambient temperature for 16 h. Most of the tetrahydrofuran wasremoved in vacuo and the resultant mixture was extracted with ethylacetate (4×50 mL). The combined organic extracts were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 10% to 20% gradient of ethylacetate in hexanes to afford tert-butyl4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-1′(2′H)-carboxylate(0.93 g, 74%) as a colorless solid: mp 154-156° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.85 (dd, J=1.8 Hz, 7.3 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.32(dd, J=8.1, 8.1 Hz, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 5.90 (d, J=4.9 Hz,2H), 4.79 (ABq, 2H), 1.53 (s, 9H); ¹³C NMR (75 MHz, DMSO-d₆) 175.4,157.1, 149.1, 148.8, 141.9, 141.8, 131.1, 129.1, 129.0, 119.0, 117.4,114.5, 103.9, 101.9, 93.2, 84.7, 78.7, 59.9, 28.1; MS (ES+) m/z 460.2(M+1), 462.2 (M+1).

EXAMPLE 18.2 Synthesis of tert-butyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate

To a stirred solution of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(2.00 g, 6.77 mmol), triethylamine (1.6 mL, 11.mmol) and4-(dimethylamino)pyridine (0.02 g, 0.16 mmol) in N,N-dimethylformamide(30 mL) was added di-tert-butyl dicarbonate (2.50 g, 11.4 mmol). Thereaction mixture was stirred at ambient temperature for 50 h, dilutedwith ethyl acetate and washed with water and brine. The organic phasewas dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyand eluted with ethyl acetate/hexanes (1/3) to afford tert-butyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indole]-1′(2′H)-carboxylate(2.12 g, 79%): mp 171-172° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.91-7.88 (m, 1H), 7.36-7.29 (m, 1H), 7.16-7.14 (m, 1H), 6.47(s, 1H), 6.39 (s, 1H), 6.26 (s, 1H), 4.75 (ABq, 2H), 4.19-4.08 (m, 4H),1.62 (s, 9H); MS (ES+) m/z 417.9 (M+23).

EXAMPLE 19 Synthesis of1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.40 g, 1.35 mmol) in anhydrous N,N-dimethylformamide (30 mL) was addedcesium carbonate (1.32 g, 4.06 mmol) and the reaction mixture wasallowed to stir at ambient temperature under nitrogen for 1 h. Potassiumiodide (0.05 g, 0.3 mmol) and6-O-tosyl-1,2,3,4-di-O-isopropylidene-α-D-galactopyranose (0.35 mL, 3.7mmol) were then added and the reaction mixture was stirred at 80° C. for72 h and concentrated in vacuo. The residue was triturated with ethylacetate and filtered through a pad of diatomaceous earth. The filtratewas concentrated in vacuo and the residue was purified by columnchromatography and eluted with a 5% to 66% gradient of ethyl acetate inhexanes to afford1-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.56 g, 77%) as a colourless solid: mp 112-118° C. (ethanol); ¹H NMR(300 MHz, CDCl₃) δ7.29-7.21 (m, 1H), 7.12-7.08 (m, 1H) 7.02-6.95 (m,2H), 6.55-6.31 (m, 2H), 5.48-5.42 (m, 1H), 4.91-4.82 (m, 1H), 4.68-4.59(m, 2H), 4.33-4.22 (m, 3H), 4.18-4.10 (m, 4H), 4.07-3.98 (m, 1H),3.88-3.80 (m, 1H), 1.38-1.26 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 177.7,177.6, 155.3, 154.9, 144.4, 144.3, 143.0, 142.9, 138.3, 138.0, 132.6,132.1, 128.5, 128.4, 123.6, 123.2, 122.9, 122.8, 121.7, 121.0, 112.4,111.9, 109.7, 109.6, 109.5, 109.2, 109.0, 108.8, 99.1, 99.0, 96.4, 96.2,80.3, 79.6, 71.6, 71.5, 71.0, 70.9, 70.5, 70.2, 65.9, 65.2, 64.5, 63.8,57.9, 57.8, 41.0, 40.8, 26.1, 26.0, 25.8, 25.5, 25.0, 24.5, 24.5; MS(ES+) m/z 538.0 (M+1).

EXAMPLE 20 Synthesis of6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose

1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.45 g, 0.83 mmol) was suspended in 80% v/v aqueous trifluoroaceticacid (40 mL) and the reaction mixture was stirred at ambient temperaturefor 3 h. The reaction mixture was concentrated in vacuo and the residuerecrystallized from ethanol to afford6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose(0.025 g, 7%) as an off white solid: mp 122-126° C. (ethanol); ¹³C NMR(75 MHz, CDCl₃) δ178.5, 155.2, 155.2, 155.1, 155.0, 144.5, 142.6, 142.2,142.1, 138.0, 138.0, 132.3, 132.0, 129.0, 123.5, 123.4, 121.0, 120.9,111.6, 111.4, 109.9, 109.7 99.2, 92.7, 79.9, 64.4, 63.8, 60.4, 58.0,21.0, 14.2; MS (ES+) m/z 480.0 (M+23).

EXAMPLE 21 Synthesis of1′-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.59 g, 2.0 mmol), cyclopropylboronic acid (0.34 g, 4.0 mmol), cupricacetate (0.36 g, 2.0 mmol) and 4-(N,N-dimethylamino)pyridine (0.73 g,6.0 mmol) in anhydrous toluene (10 mL) was added dropwise sodiumhexamethyldisilazide (1 M solution in tetrahydrofuran, 2.0 mL, 2.0mmol). The reaction vessel was fitted with a condenser topped with acalcium chloride drying tube and the mixture was heated at 95° C. for 16h. The reaction mixture was allowed to cool to ambient temperature,diluted with 1 M hydrochloric acid (40 mL) and extracted with ethylacetate (2×25 mL). The combined organic extracts were washed with brine(25 mL), dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. Trituration of the residue in diethyl ether/ethyl acetate(1/1, 20 mL) afforded1-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.48 g, 72%) as an off-white solid: mp 227-228° C. (ethylacetate/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ7.36-7.28 (m, 1H),7.18-7.11 (m, 2H), 7.08-7.02 (m, 1H), 6.48 (s, 1H), 6.14 (s, 1H), 4.88(d, J=8.9 Hz, 1H), 4.62 (d, J=8.9 Hz, 1H), 4.20-4.06 (m, 4H), 2.74-2.65(m, 1H), 1.14-0.88 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ178.1, 155.2,144.6, 143.4, 138.3, 132.0, 128.8, 123.7, 123.3, 121.3, 111.4, 109.7,99.4, 80.1, 64.6, 64.0, 58.1, 22.5, 6.4; MS (ES+) m/z 336.0 (M+1).

EXAMPLE 22 Synthesis of1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(1.00 g, 3.39 mmol), sodium acetate (0.556 g, 6.78 mmol) and aceticanhydride (20 mL) was heated at reflux for 0.5 h. The reaction mixturewas allowed to cool to ambient temperature and was concentrated invacuo. Trituration of the residue in water (20 mL), followed byrecrystallization of the resultant solid from hexanes/diethyl ether,afforded1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.802 g, 70%) as a colorless solid: mp 236-238° C. (hexanes/diethylether); ¹H NMR (300 MHz, CDCl₃) δ8.32-8.25 (m, 1H), 7.42-7.33 (m, 1H),7.25-7.15 (m, 2H), 6.52 (s, 1H), 6.25 (s, 1H), 4.97-4.90 (m, 1H),4.68-4.60 (m, 1H), 4.25-4.04 (m, 4H), 2.68 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ178.5, 171.0, 155.2, 145.1, 139.6, 138.6, 130.8, 129.4, 126.2,123.7, 121.0, 116.8, 111.7, 99.6, 80.9, 64.6, 64.0, 58.8, 26.7; MS (ES+)m/z 360.1 (M+23).

EXAMPLE 23 Synthesis of1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.753 g, 2.55 mmol), [4-(trifluoromethyl)pyridin-2-yl]methanol(Ashimori et al., Chem. Pharm. Bull. (1990) 38:2446-2458) (0.655 g, 3.70mmol) and tri-n-butylphosphine (0.93 mL, 3.7 mmol) in anhydroustetrahydrofuran (20 mL) and anhydrous dimethylsulfoxide (0.2 mL) atambient temperature was added over a period of 10 min a solution ofdiethyl azodicarboxylate (0.64 mL, 4.1 mmol) in anhydroustetrahydrofuran (10 mL). The reaction mixture was stirred at ambienttemperature for 3 h and was poured into 1 M hydrochloric acid (50 mL).The mixture was extracted with diethyl ether (3×50 mL) and the combinedorganic extracts were washed with brine (50 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. Purification of theresidue by column chromatography and eluted with a 80% to 100% gradientof dichloromethane in hexanes, followed by a 0% to 20% gradient of ethylacetate in dichloromethane and recrystallization from methanol afforded1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.164 g, 10%) as a colorless solid: mp 154-155° C. (methanol); ¹H NMR(300 MHz, CDCl₃) δ8.76 (d, J=5.1 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=5.1Hz, 1H), 7.24-7.16 (m, 2H), 7.08-7.01 (m, 1H), 6.86 (d, J=7.7 Hz, 1H),6.52 (s, 1H), 6.31 (s, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.04 (d, J=16.1 Hz,1H), 4.95 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.23-4.11 (m, 4H);¹³C NMR (75 MHz, CDCl₃) δ177.8, 157.3, 155.3, 150.8, 144.8, 141.9,139.8, 138.5, 132.3, 129.0, 124.1, 123.9, 121.1, 118.7, 117.6, 111.8,109.3, 99.5, 80.1, 64.7, 64.0, 58.2, 45.8; MS (ES+) m/z 455.0 (M+1).

EXAMPLE 24 Synthesis of4′-acetyl-t-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 10 mL septum-capped microwave pressure tube was charged with4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.39 g, 1.0 mmol), palladium (II) acetate (0.022 g, 0.1 mmol),1,3-bis(diphenylphosphino)propane (0.10 g, 0.25 mmol) and potassiumcarbonate (0.17 g, 1.2 mmol). The tube was capped and purged for 5 minwith dry nitrogen, and butyl vinyl ether (0.52 mL, 4.0 mmol),N,N-dimethylformamide (2.0 mL) and water (0.2 mL) were added. Thereaction mixture was heated for 1 h under microwave irradiation (100 W,120° C.) and was allowed to cool to ambient temperature, poured into 10%v/v aqueous hydrochloric acid (5 mL) and stirred at ambient temperaturefor 1 h. The mixture was diluted with water (20 mL) and was neutralizedwith 2 M aqueous sodium carbonate. Ethyl acetate (20 mL) was added andthe biphasic mixture was filtered through a pad of diatomaceous earth.The pad was washed with ethyl acetate (20 mL) and the filtrate wastransferred to a separatory funnel. The aqueous phase was extracted withethyl acetate (3×20 mL). The combined organic extracts were washed withwater (3×20 mL) and brine (20 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography and eluted with a 0% to 100% gradient of ethylacetate in hexanes, followed by recrystallization fromdichloromethane/diethyl ether to afford4′-acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′N)-one(0.264 g, 75%) as an off-white solid: mp 234-235° C.(dichloromethane/diethyl ether); ¹H NMR (300 MHz, CDCl₃) δ7.55-7.44 (m,2H), 7.14-7.08 (m, 1H), 6.50 (s, 1H), 5.99 (s, 1H), 4.95-4.77 (m, 2H),4.19-4.04 (m, 4H), 3.28 (m, 3H), 2.43 (m, 3H); ¹³C NMR (75 MHz, CDCl₃)δ198.3, 178.6, 157.2, 145.4, 144.3, 137.4, 134.5, 130.6, 129.5, 124.4,119.9, 112.1, 110.2, 98.9, 78.9, 64.5, 64.0, 59.4, 28.5, 27.0; MS (ES+)m/z 351.8 (M+1).

EXAMPLE 25 Synthesis of1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.25 g, 0.57 mmol) in p-dioxane (15 mL) was added thioacetamide (0.047g, 0.63 mmol) and the reaction mixture, which became homogeneous uponheating, was heated at 80° C. for 1 h. The reaction mixture was allowedto cool to ambient temperature and was concentrated to dryness in vacuo.The crude product was purified by column chromatography and eluted witha 0% to 100% gradient of ethyl acetate in hexanes to afford1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.076 g, 33%) as an off-white solid: mp 219-220° C. (hexanes/ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ7.42-7.36 (m, 1H), 7.32-7.27 (m, 1H),6.91 (d, J=7.7 Hz, 1H), 6.54 (s, 1H), 6.36 (s, 1H), 6.22 (s, 1H),4.81-4.71 (m, 2H), 4.21-4.07 (m, 4H), 3.29 (s, 3H), 2.64 (s, 3H); ¹³CNMR (75 MHz, CDCl₃) δ178.4, 165.2, 156.1, 151.8, 144.4, 137.7, 133.2,129.2, 128.6, 124.7, 122.2, 116.6, 111.2, 108.2, 99.1, 78.3, 77.4, 64.7,64.0, 58.8, 27.0, 19.1; MS (ES+) m/z 406.9 (M+1).

EXAMPLE 26 Synthesis of4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of4′-(bromoacetyl)-t-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.20 g, 0.47 mmol) in anhydrous ethanol (10 mL) was added thiourea(0.039 g, 0.51 mmol) and the reaction mixture was heated at reflux for 1h. The reaction mixture was allowed to cool to ambient temperature andwas concentrated to dryness in vacuo. The crude product was purified bycolumn chromatography and eluted with a 0% to 10% gradient of methanolin dichloromethane to afford4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.159 g, 84%) as a pale yellow solid: mp 233-234° C. (dec.)(dichloromethane/methanol); ¹H NMR (300 MHz, CDCl₃) δ7.44-7.37 (m, 1H),7.23 (d, J=7.9 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.57-6.42 (br m, 2H),6.37 (s, 1H), 6.22 (s, 1H), 5.80 (s, 1H), 4.80-4.73 (m, 2H), 4.22-4.07(m, 4H), 3.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 178.0, 168.2, 155.7,144.8, 144.4, 138.1, 129.7, 129.4, 124.3, 121.9, 111.4, 109.4, 105.9,99.2, 78.4, 77.4, 64.7, 64.0, 58.6, 27.1; MS (ES+) m/z 408.3 (M+1).

EXAMPLE 27 Synthesis of4′-(5-hydroxy-1H-pyrazol-3-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a suspension of4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.23 g, 0.53 mmol) in glacial acetic acid (5 mL) was added dropwisehydrazine hydrate (0.03 mL, 0.59 mmol) and the reaction mixture washeated at reflux for 16 h, allowed to cool to ambient temperature andwas concentrated in vacuo. The crude product was triturated indichloromethane (10 mL) and the resultant solid was recrystallized fromdichloromethane/diethyl ether. Following a second recrystallization frommethanol,4′-(5-hydroxy-1H-pyrazol-3-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.029 g, 14%) was obtained as a colorless solid: mp>250° C. (methanol);¹H NMR (300 MHz, DMSO-d₆) δ 11.77 (br s, 1H), 9.51 (br s, 1H), 7.49-7.39(m, 1H), 7.22-7.09 (m, 2H), 6.41 (s, 1H), 6.15 (s, 1H), 4.76-4.42 (m,3H), 4.25-4.02 (m, 4H), 3.19 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.1,155.0, 144.7, 144.0, 137.2, 129.1, 126.5, 123.1, 121.8, 110.6, 108.8,98.7, 90.6, 76.2, 64.2, 63.6, 57.7, 26.5; MS (ES+) m/z 391.8 (M+1).

EXAMPLE 28 Synthesis of1′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A solution of3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide(0.50 g, 1.17 mmol) and N,N-dimethylacetamide dimethyl acetal (0.60 mL,4.1 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 3 h, allowedto cool to ambient temperature and concentrated in vacuo. Hydroxylaminehydrochloride (0.11 g, 1.6 mmol), 1,4-dioxane (10 mL), glacial aceticacid (10 mL) and 2 M aqueous sodium hydroxide (0.85 mL, 1.70 mmol) werethen added and the mixture was heated at 90° C. for 2 h. The mixture wasallowed to cool to ambient temperature and water was added, causing aprecipitate to be deposited. The solid was collected by filtration,washed with water and hexanes and recrystallized fromdichloromethane/hexanes to afford1′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.038 g, 6%) as a colorless solid: mp 80-89° C.(dichloromethane/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 8.09-8.12 (m, 2H),7.54-7.57 (m, 2H), 7.15-7.18 (m, 2H), 7.00-7.03 (m, 1H), 6.74-6.77 (m,1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.14-5.17 (m, 1H), 4.89-4.92 (m, 2H),4.65-4.67 (m, 1H), 4.13-4.17 (m, 4H), 2.43 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 177.6, 174.9, 167.9, 155.3, 144.7, 141.7, 138.4, 137.0, 132.3,131.4, 129.9, 128.9, 127.4, 126.8, 124.8, 124.1, 123.7, 120.8, 111.6,109.1, 99.5, 80.2, 64.5, 63.9, 58.1, 43.7, 11.7; MS (ES+) m/z 467.8(M+1).

EXAMPLE 29 Synthesis of3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile

To a solution of3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.35 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (20 mL) at 0° C.was added slowly sodium hydride (60% w/w dispersion in mineral oil,0.072 g, 1.50 mmol). The solution was stirred at ambient temperature for30 min, 5-(4-(bromomethyl)phenyl)isoxazole (Sasaki et al., Biorg. Med.Chem. Lett. (1998) 8:2241-2246) (0.24 g, 1.00 mmol) was added and themixture was stirred for 16 h at ambient temperature. The reactionmixture was poured into water (200 mL) and extracted with ethyl acetate(3×200 mL). The combined organic extracts were washed with brine (3×100mL), dried over magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography and eluted with a 15%to 50% gradient of ethyl acetate in hexanes to afford3-{4-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]phenyl}-3-oxopropanenitrile(0.33 g, 61%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 7.96-7.92(m, 2H), 7.63-7.60 (m, 2H), 7.50-7.46 (m, 1H), 7.23-7.13 (m, 2H), 7.046.97 (m, 2H), 6.71-6.67 (m, 1H), 5.43-4.76 (m, 4H), 4.06 (s, 2H), 2.46(s, 3H).

EXAMPLE 29.1 Synthesis of1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onehydrochloride

To a solution of3-(4-((3-methyl-2′-oxo-6H-spiro[benzofuro[5,6-d]isoxazole-5,3′-indoline]-1′-yl)methyl)phenyl)-3-oxopropanenitrilein ethanol (20 mL) was added hydrazine hydrate (0.40 mL, 15 mmol). Thesolution was heated at reflux for 4 h, allowed to cool to ambienttemperature and concentrated in vacuo. The resultant solid was dissolvedin anhydrous methanol (10 mL) and a saturated solution of hydrogenchloride in anhydrous methanol (1.5 mL) was added, causing a precipitateto be deposited. The solid was collected by filtration to obtain1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.14 g, 43%) as a pale yellow solid: mp 191-195° C. (methanol); ¹H NMR(300 MHz, DMSO-d₆) δ 7.82-7.71 (m, 3H), 7.52 (d, J=8.3 Hz, 2H),7.31-7.18 (m, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.04-6.97 (m, 2H), 6.40 (s,1H), 5.16 (d, J=16.3 Hz, 1H), 5.05 (d, J=9.7 Hz, 1H), 4.98-4.89 (m, 2H),2.42 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.3, 164.3, 157.8, 155.9,145.7, 142.7, 138.0, 130.5, 129.7, 128.3, 127.5, 126.6, 124.7, 124.4,123.8, 117.8, 109.2, 108.5, 108.4, 81.5, 56.1, 43.5, 9.8; MS (ES+) m/z463.9 (M+1). Anal. Calcd. for C₂₇H₂₁N₆O₃.1.6HCl: C, 62.15; H, 4.37; N,13.42. Found: C, 61.97; H, 4.52; N, 13.15.

EXAMPLE 29.2 Synthesis of1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 29 and EXAMPLE 29.1 andmaking non-critical variations using2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one toreplace3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride was obtained (25%) as a pale yellow solid: mp 198-201° C.(methanol); ¹H NMR (300 MHz, DMSO-d₆)

7.79 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.21-7.25 (m, 1H), 7.15(d, J=7.1 Hz, 1H), 7.00 (t, J=7.8 Hz, 2H), 6.50 (s, 1H), 6.38 (s, 1H),6.08 (s, 1H), 5.06-4.86 (m, 2H), 4.80 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3Hz, 1H), 4.21-4.01 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.3, 155.2,145.6, 144.7, 142.6, 138.3, 138.3, 132.2, 129.3, 128.4, 127.6, 126.7,124.2, 123.7, 121.6, 111.4, 109.9, 99.3, 80.0, 64.7, 64.1, 57.7, 43.3;MS (ES+) m/z 467.0 (M+1). Anal. Calcd. for C₂₇H₂₂N₄O₄.1.5HCl: C, 62.22;H, 4.54; N, 10.75. Found: C, 62.19; H, 4.59; N, 10.55.

EXAMPLE 30 Synthesis of1′-[4(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid (0.75 g, 1.7 mmol) in dichloromethane (10 mL) was added oxalylchloride (0.50 mL, 5.77 mmol) and N,N-dimethylformamide (2 drops,catalytic amount). The mixture was stirred for 16 h at ambienttemperature and concentrated in vacuo. The residue was dissolved inpyridine (1 mL) and transferred into a 10 mL microwave reaction vesselwith pyridine rinses (2×1 mL). To this solution was addedN-hydroxyacetamidine (0.25 g, 3.4 mmol) and the reaction mixture wasirradiated at 170° C. for 30 min in a microwave reactor. The reactionmixture was allowed to cool to ambient temperature, concentrated invacuo and the residue was purified by column chromatography and elutedwith a 15% to 50% gradient of ethyl acetate in hexanes, followed byrecrystallization from dichloromethane/diethyl ether to afford1′-[4(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.50 g, 63%) as a colorless solid: mp 177-178° C. (dichloromethane); ¹HNMR (300 MHz, CDCl₃) δ 8.08 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H),7.26-7.13 (m, 2H), 7.06-6.98 (m, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.49 (s,1H), 6.21 (s, 1H), 5.14 (d, J=16.0 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.87(d, J=16.0 Hz, 1H), 4.66 (d, J=8.9 Hz, 1H), 4.21-4.07 (m, 4H), 2.44 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 177.6, 174.9, 167.8, 155.3, 144.7, 141.7,138.4, 132.2, 128.9, 128.6, 128.0, 124.1, 123.8, 123.8, 120.8, 111.5,109.1, 99.5, 80.1, 64.5, 63.9, 58.1, 43.9, 11.7; MS (ES+) m/z 467.9(M+1).

EXAMPLE 31 Synthesis of2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide

To a suspension of2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile(0.24 g, 0.57 mmol) in ethanol (20 mL) was added 3 M aqueous sodiumcarbonate (2 mL) and 30% w/w aqueous hydrogen peroxide (2 mL). Thereaction mixture was stirred at ambient temperature for 16 h andconcentrated in vacuo. The residue was triturated in water to afford2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide(0.23 g, 93%) as a colorless solid: mp 220-222° C. (water); ¹H NMR (300MHz, CDCl₃) δ 8.46-8.42 (m, 1H), 7.82 (s, 1H), 7.81-7.74 (m, 2H), 7.65(d, J=1.5 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.0, 5.0 Hz, 1H),7.19 (s, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H),5.14-4.97 (ABq, 2H), 4.81-4.68 (ABq, 2H), 4.19-4.06 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 177.6, 167.6, 155.4, 155.1, 149.7, 145.7, 144.7, 138.3,137.6, 132.4, 129.4, 129.2, 123.3, 123.3, 122.3, 121.6, 112.1, 109.3,99.2, 79.8, 64.7, 64.1, 57.7, 45.3; MS (ES+) m/z 429.9 (M+1).

EXAMPLE 32 Synthesis of1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A 10 mL microwave reaction vessel was charged with1-[(6-chloropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.13 g, 0.31 mmol) and morpholine (0.5 mL, 6.1 mmol). The reactionmixture was irradiated at 180° C. for 20 min in a microwave reactor. Thereaction mixture was poured into a mixture of water (15 mL) and ethylacetate (30 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×30 mL). The combined organic layers waswashed with brine (40 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with 50% ethyl acetate in hexanes to afford1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.13 g, 92%) as a colorless solid: mp 117-119° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.22-8.19 (m, 1H), 7.56-7.49 (m, 1H), 7.32-7.24 (m, 1H),7.18-7.08 (m, 2H), 7.06-6.99 (m, 1H), 6.87-6.80 (m, 1H), 6.52 (s, 1H),6.02 (s, 1H), 4.81 (q, J=15.5 Hz, 2H), 4.72 (ABq, J=40.6, 9.3 Hz, 2H),4.22-4.06 (m, 4H), 3.70-3.63 (m, 4H), 3.44-3.38 (m, 4H); ¹³C NMR (75MHz, DMSO-d₆) δ 176.6, 158.5, 154.6, 146.7, 144.1, 141.9, 137.7, 137.1,131.7, 128.7, 123.6, 123.0, 121.1, 121.0, 110.8, 109.4, 107.1, 98.8,79.3, 65.8, 64.1, 63.5, 57.1, 45.0; MS (ES+) m/z 471.9 (M+1).

EXAMPLE 32.1 Synthesis of1′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 32 and makingnon-critical variations using dimethylamine (40% w/w in water) toreplace morpholine,1′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (82%) as a colorless solid: mp 93-95° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.18-8.14 (m, 1H), 7.49-7.43 (m, 1H), 7.31-7.24 (m, 1H),7.18-7.07 (m, 2H), 7.05-6.98 (m, 1H), 6.65-6.59 (m, 1H), 6.52 (s, 1H),6.02 (s, 1H), 4.87-4.62 (m, 4H), 4.21-4.07 (m, 4H), 2.98 (s, 6H); ¹³CNMR (75 MHz, DMSO-d₆) δ 176.6, 158.4, 154.6, 146.9, 144.1, 141.9, 137.7,136.7, 131.7, 128.7, 123.5, 122.9, 121.1, 118.8, 110.8, 109.4, 105.8,98.7, 79.3, 64.1, 63.5, 57.2, 37.6; MS (ES+) m/z 429.9 (M+1).

EXAMPLE 32.2 Synthesis of1-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 32 and makingnon-critical variations using dimethylamine (40% w/w in water) toreplace morpholine and1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-[(6-chloropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (44%) as a colorless solid: mp 196-197° C.; ¹H NMR (300MHz, CDCl₃) δ7.45-7.34 (m, 1H), 7.24-7.11 (m, 2H), 7.06-6.94 (m, 2H),6.52-6.46 (m, 2H), 6.42-6.35 (m, 1H), 6.28 (s, 1H), 4.91 (ABq, J=53.2,15.3 Hz, 2H), 4.80 (ABq, J=84.8, 9.1 Hz, 2H), 4.23-4.07 (m, 4H), 3.04(s, 6H); ¹³C NMR (300 MHz, CDCl₃) δ 177.4, 159.0, 155.3, 153.3, 144.5,142.7, 138.2, 137.9, 132.2, 128.6, 123.5, 123.1, 121.2, 111.7, 109.9,108.8, 104.5, 99.3, 80.3, 64.5, 63.9, 58.1, 46.0, 37.8; MS (ES+) m/z430.0 (M+1).

EXAMPLE 33 Synthesis of1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A mixture of1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-2′(1′H)-one(0.2 g, 0.5 mmol) and sodium tert-butoxide (0.06 g, 0.67 mmol) in1,2-dimethoxyethane (3 mL) was degassed with argon for 15 min.(R)-(−)-1′-[(S)-2-(dicyclohexylphosphino)ferrocenyl}ethyldi-tert-butylphosphine(0.006 g, 0.01 mmol), palladium(II) acetate (0.01 g, 0.05 mmol), andbenzophenone imine (0.1 mL, 0.6 mmol) were added. The reaction mixturewas stirred at 70° C. for 24 h, allowed to cool to ambient temperature,diluted with dichloromethane (20 mL) and filtered through a pad ofdiatomaceous earth. The pad was washed with dichloromethane (20 mL) andthe filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 25% to 35% gradient of ethylacetate in hexanes to afford1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.19 g, 70%) as a colorless solid: MS (ES+) m/z 565.8 (M+1).

EXAMPLE 33.1 Synthesis of tert-butyl(3R)-3-({4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]phenyl}amino)pyrrolidine-1-carboxylate

To a solution of1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one(0.44 g, 1.0 mmol) in anhydrous toluene (10 mL) was added(±)-(1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) (0.093 g, 0.15mmol) and (R)-(+)-1-Boc-3-aminopyrrolidine (0.26 g, 1.4 mmol), followedby tris(dibenzylideneacetone)dipalladium (0) (0.458 g, 0.1 mmol) andsodium tert-butoxide (0.19 g, 2.0 mmol). The reaction mixture was heatedat reflux for 16 h, allowed to cool to ambient temperature and filteredthrough a pad of diatomaceous earth. The filtrate was concentrated invacuo and the residue dissolved in ethyl acetate (100 mL). The mixturewas washed with water (2×75 mL) and brine (75 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 20% to 40% gradient of ethylacetate in hexanes to afford tert-butyl(3R)-3-({4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]phenyl}amino)pyrrolidine-1-carboxylate(0.403 g, 74%) as a brown oil: ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.11 (m,4H), 7.05-7.00 (m, 1H), 6.89 (d, J=7.7 Hz, 1H), 6.78 (dd, J=10.3, 6.3Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 6.49 (dd, J=7.9, 7.9 Hz, 1H),5.02-4.93 (m, 2H), 4.74-4.69 (m, 2H), 4.01 (br s, 1H), 3.76-3.68 (m,2H), 3.46 (m, 2H), 3.20 (m, 1H), 2.21-2.12 (m, 1H), 1.87 (br s, 1H),1.46 (s, 9H).

EXAMPLE 33.2 Synthesis of5,6-difluoro-1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride

Following the procedure as described in EXAMPLE 11.111 and makingnon-critical variations using tert-butyl(3R)-3-({4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]phenyl}amino)pyrrolidine-1-carboxylateto replace tert-butyl4-[(5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate,5,6-difluoro-1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-onehydrochloride was obtained (78%) as a beige solid: mp 153-162° C.; ¹HNMR (300 MHz, CDCl₃) δ 7.36-7.27 (m, 3H), 7.19 (d, J=7.3 Hz, 1H), 7.10(d, J=7.4 Hz, 1H), 7.06-6.97 (m, 3H), 6.92 (dd, J=10.7, 6.4 Hz, 1H),6.53 (dd, J=8.4, 8.4 Hz, 1H), 5.02-4.77 (m, 4H), 4.31 (s, 1H), 3.54-3.35(m, 4H), 2.37 (s, 1H), 2.16 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 178.6,158.4 (d, J_(C-F)=10.7 Hz), 152.3 (dd, J_(C-F)=246.1, 12.8 Hz), 146.6(dd, J_(C-F)=239.5, 13.4 Hz), 143.3, 141.0, 133.4, 132.4, 130.5, 130.4,125.5 (d, J_(C-F)=3.3 Hz), 125.0, 124.9, 120.2, 112.7 (d, J_(C-F)=20.3Hz), 111.3, 100.8 (d, J_(C-F)=22.5 Hz), 82.1, 59.1, 57.7, 50.2, 46.3,44.7, 30.4; MS (ES+) m/z 448.2 (M+1). Anal. Calcd forC₂₆H₂₃F₂N₃O₂.2.3HCl: C, 58.77; H, 4.80; N, 7.91. Found: C, 58.69; H,4.37; N, 8.33.

EXAMPLE 33.3 Synthesis of1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 33.1 and makingnon-critical variations using morpholine to replace(R)-(+)-1-Boc-3-aminopyrrolidine, and1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (60%) as a pale yellow solid: mp 204-206° C.; ¹H NMR (300MHz, CDCl₃) δ8.23 (d, J=2.4 Hz, 1H), 7.23-7.11 (m, 4H), 7.01 (dd, J=7.5,7.5 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.13(d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.89 (d, J=15.6 Hz, 1H),4.66 (d, J=9.0 Hz, 1H), 4.21-4.11 (m, 4H), 3.87 (t, J=4.8 Hz, 4H), 3.17(t, J=5.0 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 177.4, 155.3, 146.3, 146.2,144.6, 142.2, 138.3, 137.3, 132.2, 128.8, 123.7, 123.4, 123.2, 122.0,121.1, 111.7, 109.7, 99.4, 80.2, 66.6, 64.5, 63.9, 58.1, 48.5, 45.6; MS(ES+) m/z 472.2 (M+1).

EXAMPLE 33.4 Synthesis of1′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 33.1 and makingnon-critical variations using dimethylamine hydrochloride to replace(R)-(+)-1-Boc-3-aminopyrrolidine, and1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one,1′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (23%) as a beige solid: mp 229-236° C.; ¹H NMR (300 MHz,CDCl₃) δ8.06 (d, J=2.7 Hz, 1H), 7.22-6.92 (m, 6H), 6.50 (s, 1H), 6.27(s, 1H), 5.11 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.87 (d,J=15.3 Hz, 1H), 4.65 (d, J=8.7 Hz, 1H), 4.21-4.11 (m, 4H), 2.96 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ177.4, 155.3, 145.5, 144.5, 142.8, 142.4,138.3, 134.1, 132.3, 128.8, 123.6, 123.2, 122.0, 121.2, 119.8, 111.7,109.9, 99.3, 80.2, 64.5, 63.9, 58.1, 45.7, 40.1; MS (ES+) m/z 430.1(M+1).

EXAMPLE 34 Synthesis of1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a solution of1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.18 g, 0.32 mmol) in tetrahydrofuran (10 mL) was added 2 M aqueoushydrochloric acid (0.5 mL). The reaction mixture was stirred at ambienttemperature for 10 min, cooled to 0° C. and saturated aqueous sodiumbicarbonate (10 mL) was added. The mixture was diluted with ethylacetate (30 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×25 mL). The combined organic layers waswashed with brine (45 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography and eluted with 65% ethyl acetate in hexanes to afford1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.10 g, 76%) as a colorless solid: mp 240-241° C.; ¹H NMR (300 MHz,CDCl₃) δ7.45-7.35 (m, 1H), 7.25-7.14 (m, 2H), 7.06-6.98 (m, 1H),6.91-6.86 (m, 1H), 6.59-6.54 (m, 1H), 6.50 (s, 1H), 6.45-6.39 (m, 1H),6.37 (s, 1H), 5.12-5.03 (m, 1H), 4.99-4.92 (m, 1H), 4.80-4.63 (m, 4H),4.25-4.05 (m, 4H); ¹³C NMR (300 MHz, CDCl₃) δ 177.5, 157.9, 155.2,153.0, 144.6, 142.1, 139.0, 138.2, 132.2, 128.8, 123.7, 123.4, 121.2,111.7, 111.1, 109.6, 107.9, 99.3, 80.0, 64.5, 63.9, 58.1, 45.2; MS (ES+)m/z 401.9 (M+1).

EXAMPLE 35 Synthesis of1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a stirred mixture of1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.24 g, 0.58 mmol), sodium iodide (0.29 g, 1.9 mmol), and water (2drops) in acetonitrile (5 mL) was added chlorotrimethylsilane (0.23 mL,1.8 mmol). The reaction mixture was stirred at ambient temperature for16 h. Further, sodium iodide (0.14 g, 0.95 mmol) andchlorotrimethylsilane (0.12 mL, 0.95 mmol) were added and the reactionmixture was stirred at ambient temperature for 24 h. Further, sodiumiodide (0.29 g, 1.9 mmol) and chlorotrimethylsilane (0.23 mL, 1.8 mmol)were added and the reaction mixture was stirred at ambient temperaturefor 5 days. A solution of sodium bisulfite (0.51 g, 4.9 mmol) in water(30 mL) and ethyl acetate (150 mL) were added. The layers were separatedand the organic layer was washed with brine (2×50 mL), dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was triturated with diethyl ether and the crude product waspurified by preparative thin layer chromatography and eluted with 30%acetone in dichloromethane to afford1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.15 g, 63%) as a colorless solid: mp 249-250° C.; ¹H NMR (300 MHz,CDCl₃) δ7.61-7.46 (m, 2H), 7.31-7.21 (m, 1H), 7.20-7.14 (m, 1H),7.09-7.02 (m, 1H), 6.86-6.81 (m, 1H), 6.66-6.59 (m, 1H), 6.50 (s, 1H),6.15 (s, 1H), 4.92-4.60 (m, 4H), 4.24-4.06 (m, 4H); ¹³C NMR (75 MHz,CDCl₃) δ 177.7, 164.4, 155.2, 144.7, 142.2, 141.4, 138.3, 133.5, 132.2,129.0, 124.2, 123.8, 120.9, 120.7, 115.8, 111.4, 108.7, 99.5, 80.0,64.5, 63.9, 58.0, 40.6; MS (ES+) m/z 403.0 (M+1).

EXAMPLE 35.1 Synthesis of1′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 35 and makingnon-critical variations using1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneto replace1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,1′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onewas obtained (19%) as a colorless solid: mp>250° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.31 (s, 2H), 7.37-7.28 (m, 1H), 7.28-7.21 (m, 1H), 7.20-7.12(m, 1H), 7.10-7.00 (m, 1H), 6.50 (s, 1H), 6.08 (s, 1H), 4.71 (s, 2H),4.71 (ABq, J=47.0, 9.4 Hz, 2H), 4.23-4.04 (m, 4H); ¹³C NMR (300 MHz,CDCl₃) δ 176.9, 154.7, 144.2, 141.7, 137.8, 131.9, 128.8, 123.7, 123.2,121.2, 112.1, 111.0, 109.3, 98.8, 79.4, 64.2, 63.6, 57.2, 37.6; MS (ES+)m/z 403.9 (M+1).

EXAMPLE 36 Synthesis of1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a cooled (0° C.) solution of1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.07 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (3 mL) was addedsodium hydride (60% in mineral oil, 0.01 g, 0.25 mmol). The mixture wasstirred at ambient temperature for 1 h, and iodomethane (0.02 mL, 0.27mmol) was added. The mixture was stirred at ambient temperature for 16h, diluted with water (15 mL) and extracted with ethyl acetate (3×30mL). The combined organic layers was washed with brine (35 mL), driedover anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography and eluted with a 10%to 30% gradient of acetone in dichloromethane to afford1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.03 g, 42%) as a colorless solid: mp 205-207° C.; ¹H NMR (300 MHz,CDCl₃) δ7.40-7.34 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.16 (m, 1H),7.11-7.04 (m, 1H), 6.91-6.85 (m, 1H), 6.60-6.54 (m, 1H), 6.50 (s, 1H),6.12 (s, 1H), 4.77 (ABq, J=75.6, 9.0 Hz, 2H), 4.66 (ABq, J=58.2, 15.3Hz, 2H), 4.22-4.08 (m, 4H), 3.53 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ177.7, 162.5, 155.2, 144.7, 141.5, 139.6, 138.3, 137.4, 132.2, 128.9,124.3, 123.8, 121.3, 120.7, 114.0, 111.2, 108.5, 99.5, 79.8, 64.5, 63.9,57.9, 40.8, 37.9; MS (ES+) m/z 416.9 (M+1).

EXAMPLE 37 Synthesis of1′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a cooled (0° C.) suspension of tent-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate(0.27 g, 0.53 mmol) in anhydrous dichloromethane (12 mL) was addedtrifluoroacetic acid (4 mL). The mixture was stirred at ambienttemperature for 3 h and concentrated in vacuo. The residue was dissolvedin dichloromethane (100 mL), washed with saturated aqueous sodiumbicarbonate (35 mL) and brine (35 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford1-′[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.20 g, 93%) as a colorless solid: mp 117-119° C.; ¹H NMR (300 MHz,DMSO-d₆) 8.00-7.96 (m, 1H), 7.37-7.24 (m, 2H), 7.19-7.07 (m, 2H),7.07-6.98 (m, 1H), 6.52 (s, 1H), 6.43-6.38 (m, 1H), 6.01-5.96 (m, 3H),4.82-4.62 (m, 4H), 4.21-4.07 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 176.6,159.2, 154.6, 147.0, 144.1, 141.9, 137.7, 136.7, 131.7, 128.7, 123.5,122.9, 121.2, 119.3, 110.7, 109.4, 108.0, 98.7, 79.2, 64.1, 63.5, 57.1;MS (ES+) m/z 401.9 (M+1).

EXAMPLE 38 Synthesis ofN′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide

To a solution of1′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.40 g, 1.0 mmol) in 2-propanol was added N,N-dimethylformamidedimethyl acetal (0.17 mL, 1.3 mmol). The mixture was heated at refluxfor 3 h, allowed to cool to ambient temperature and furtherN,N-dimethylformamide dimethyl acetal (0.12 mL, 0.9 mmol) was added. Themixture was heated at reflux for 6 h and allowed to cool to 50° C.Hydroxylamine hydrochloride (0.15 g, 2.2 mmol) was added and the mixturewas stirred at 50° C. for 16 h. The mixture was allowed to cool toambient temperature, during which time a precipitate was deposited. Thesolid was filtered, washed with 2-propanol and diethyl ether and driedto affordN′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide(0.37 g, 82%) as a colorless solid: mp 231-232° C.; ¹H NMR (300 MHz,DMSO-d₆) δ10.07 (s, 1H), 9.41-9.35 (m, 1H), 8.23-8.19 (m, 1H), 7.84-7.78(m, 1H), 7.59-7.53 (m, 1H), 7.32-7.24 (m, 1H), 7.19-7.13 (m, 1H),7.13-7.07 (m, 1H), 7.07-6.99 (m, 2H), 6.52 (s, 1H), 6.05 (s, 1H),4.86-4.83 (m, 2H), 4.73 (ABq, J=44.3, 9.4 Hz, 2H), 4.22-4.06 (m, 4H);¹³C NMR (75 MHz, DMSO-d₆) δ 176.7, 154.6, 152.0, 146.6, 144.1, 141.8,137.7, 137.5, 135.4, 131.7, 128.7, 124.0, 123.6, 123.0, 121.1, 110.8,110.4, 109.4, 98.8, 79.3, 64.1, 63.5, 57.2; MS (ES+) m/z 444.9 (M+1).

EXAMPLE 39 Synthesis of1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

To a cooled (0° C.) suspension ofN′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide(0.22 g, 0.5 mmol) in tetrahydrofuran (7 mL) was slowly addedtrifluoroacetic anhydride (0.08 mL, 0.54 mmol). The mixture was stirredat ambient temperature for 3 h, diluted with saturated aqueous sodiumbicarbonate (10 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers was washed with saturated aqueous sodiumbicarbonate (50 mL) and brine (50 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography and eluted with a 50% to 65% gradient of ethylacetate in hexanes to afford1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.11 g, 54%) as a colorless solid: mp 207-209° C.; ¹H NMR (300 MHz,DMSO-d₆) δ8.65 (s, 1H), 8.37 (s, 1H), 7.82-7.77 (m, 1H), 7.61-7.55 (m,1H), 7.30-7.17 (m, 2H), 7.11-7.04 (m, 1H), 6.90-6.85 (m, 1H), 6.52 (s,1H), 6.18 (s, 1H), 5.03 (ABq, J=40.9, 15.6 Hz, 2H), 4.80 (ABq, J=79.6,9.0 Hz, 2H), 4.23-4.09 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.7,155.2, 154.2, 149.9, 144.8, 141.2, 138.4, 132.1, 129.8, 129.0, 127.0,124.4, 124.0, 123.0, 120.5, 117.4, 111.4, 108.6, 99.5, 80.0, 64.5, 63.9,58.0, 41.2; MS (ES+) m/z 426.9 (M+1).

EXAMPLE 40 Synthesis of1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

A solution of1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.66 g, 1.61 mmol) in glacial acetic acid (10 mL) and water (5 mL) wasstirred at ambient temperature for 18 h and concentrated in vacuo. Theresidue was recrystallized from ethyl acetate to afford1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.59 g, 99%): mp 179-181° C. (ethyl acetate/hexane); ¹H NMR (300 MHz,DMSO-d₆) δ 7.30-7.25 (m, 1H), 7.13-7.07 (m, 2H), 7.01-6.95 (m, 1H), 6.46(s, 1H), 6.21-6.19 (m, 1H), 5.02-4.94 (m, 1H), 4.71-4.57 (m, 3H),4.14-4.06 (m, 4H), 3.81-3.54 (m, 3H), 3.39-3.32 (m, 2H); MS (ES+) m/z369.9 (M+1).

EXAMPLE 41 AND EXAMPLE 42 Synthesis of6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrileand6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide

A mixture of1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(0.50 g, 1.2 mmol), sodium cyanide (0.12 g, 2.4 mmol) and nickel(II)bromide trihydrate (0.026 g, 1.2 mmol) in 1-methyl-2-pyrrolidinone (5mL) was heated under microwave irradiation at 200° C. for 30 min,allowed to cooled to ambient temperature, diluted with ethyl acetate andwashed with water and brine. The organic phase was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography and eluted with ethylacetate/hexanes (1/1) to afford two products:

The first compound to elute was6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrile(0.23 g, 48%): mp 213-215° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 8.06-8.01 (m, 1H), 7.95-7.92 (m, 1H), 7.71-7.67 (m, 1H),7.26-7.14 (m, 2H), 7.04-6.98 (m, 1H), 6.94-6.90 (m, 1H), 6.48 (s, 1H),6.25 (s, 1H), 5.09 (ABq, 2H), 4.71 (ABq, 2H), 4.15-4.06 (m, 4H); MS(ES+) m/z 412.0 (M+1).

The second compound to elute was6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide(0.06 g, 12%): mp 113-115° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 7.97-7.88 (m, 2H), 7.71-7.68 (m, 2H), 7.50-7.46 (m, 1H),7.27-6.99 (m, 4H), 6.48 (s, 1H), 6.12 (s, 1H), 5.06 (ABq, 2H), 4.79(ABq, 2H), 4.15-4.06 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 177.2, 165.9,155.4, 155.1, 144.6, 143.0, 139.3, 138.3, 132.0, 129.2, 124.5, 124.1,121.6, 121.1, 111.6, 109.9, 99.2, 79.9, 64.6, 64.0, 57.7, 45.2; MS (ES+)m/z 430.0 (M+1).

EXAMPLE 43 Synthesis ofN′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide

To a stirred solution of6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.84 g, 2.10 mmol) and hydroxylamine hydrochloride (0.20 g, 2.9 mmol)in ethanol (50 mL) was added triethylamine (0.40 mL, 2.9 mmol). Thereaction mixture was stirred at reflux for 18 h and concentrated invacuo. The residue was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with water and brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to affordN′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide(0.90 g, 99%): MS (ES+) m/z 431.9 (M+1).

EXAMPLE 44 Synthesis of3-amino-1′-(4-methoxybenzyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

To a solution ofN′,6-dihydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carboximidamide(0.90 g, 2.1 mmol) and triphenylphosphine (0.71 g, 2.7 mmol) intetrahydrofuran (30 mL) was added diethyl azodicarboxylate (0.43 mL, 2.7mmol) at 0° C. The reaction mixture was allowed to warm to ambienttemperature and was stirred for 16 h. 10% w/v aqueous sodium hydroxide(10 mL) was added and the mixture was stirred for 3 h. Most of thetetrahydrofuran was removed in vacuo and the resultant mixture wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with water and brine, dried over anhydrous sodium sulfateand filtered. The filtrate was concentrated in vacuo. The residue waspurified by column chromatography to afford3-amino-1′-(4-methoxybenzyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.16 g, 19%): mp 214-216° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.29-7.20 (m,5H), 7.14-7.12 (m, 1H), 7.05 (s, 1H), 7.02-6.98 (m, 2H), 6.90-6.87 (m,2H), 6.29 (s, 1H), 4.92-4.69 (m, 4H), 3.69 (s, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.3, 162.8, 159.1, 155.3, 148.8, 142.6, 138.1, 132.5,129.1, 128.7, 124.5, 124.1, 123.4, 114.5, 109.9, 109.2, 93.0, 79.9,57.9, 55.5, 42.9; MS (ES+) m/z 413.9 (M+1).

EXAMPLE 44.1 Synthesis of3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

To a stirred solution of6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.40 g, 2.7 mol) and acetohydroxamic acid (0.60 g, 8.0 mmol) inN,N-dimethylformamide (20 mL) was added cesium carbonate (2.60 g, 8.0mmol). The reaction mixture was stirred at ambient temperature for 18 hand water was added. The aqueous phase was extracted with ethyl acetate.The combined organic extracts were washed with water and brine, driedover anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyand eluted with (ethyl acetate/hexanes (2/3)+0.1% v/v 7 N methanolicammonia) to afford3-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.05 g, 5%): mp 190-192° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 8.54-8.52 (m, 1H), 7.79-7.73 (m, 1H), 7.35-7.20 (m, 5H),7.08-6.96 (m, 3H), 6.15 (s, 2H), 5.09-4.85 (m, 4H); ¹³C NMR (75 MHz,DMSO-d₆) δ 177.2, 164.2, 163.3, 158.7, 155.6, 149.9, 143.5, 137.6,131.7, 129.4, 126.4, 124.5, 123.6, 123.1, 121.9, 116.8, 111.5, 109.9,91.4, 81.0, 56.8, 45.3; MS (ES+) m/z 384.9 (M+1).

EXAMPLE 44.2 Synthesis of3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

To a stirred solution of6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.59 g, 1.6 mol) and acetone oxime (0.35 g, 4.8 mmol) inN,N-dimethylformamide (20 mL) was added cesium carbonate (1.56 g, 4.8mmol). The reaction mixture was stirred at ambient temperature for 19 h,then heated at 60° C. for 7 h and allowed to cool to ambienttemperature. Water was added and the mixture was extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with waterand brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo. The residue was dissolved in amixture of ethanol (30 mL), water (10 mL), and concentrated hydrochloricacid (2 mL) and stirred at reflux for 4 h. The mixture was allowed tocool to ambient temperature and neutralized with saturated aqueoussodium bicarbonate. The mixture was extracted with ethyl acetate (3×100mL). The combined organic extracts were washed with water and brine,dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo. The residue was subjected to columnchromatography and eluted with (ethyl acetate/hexanes (1/3)+0.1% v/v 7 Nmethanolic ammonia) to afford3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.37 g, 60%): mp 116-119° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,CDCl₃) δ 7.35-7.32 (m, 1H), 7.13-7.02 (m, 3H), 6.09 (s, 1H), 6.84-6.81(m, 1H), 4.91 (ABq, 2H), 4.31-4.25 (m, 1H), 4.13-4.09 (m, 2H), 3.86-3.66(m, 4H), 2.12-1.87 (m, 4H); (ES+) m/z 377.9 (M+1).

EXAMPLE 44.3 Synthesis of3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 44.2 and makingnon-critical variations using6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace6-fluoro-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile,3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-onewas obtained (62%): mp 262-264° C. (ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆+CDCl₃) δ 7.68-7.65 (m, 1H), 7.56-7.51 (m, 1H), 7.39-7.34 (m,1H), 7.25 (s, 1H), 7.18-7.13 (m, 3H), 7.02-6.97 (m, 1H), 6.76 (s, 1H),6.61-6.58 (m, 1H), 5.62 (s, 2H), 5.19-4.79 (m, 4H); MS (ES+) m/z 452.1(M+1).

EXAMPLE 45 Synthesis of6-hydroxy-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

To a stirred solution of concentrated sulfuric acid (2.5 mL) in water(1.5 mL) was added sodium nitrite (0.10 g, 1.5 mmol) in small portionsat 0° C., followed by hypophosphorous acid (0.50 mL, 4.6 mmol) and asolution of3-amino-t-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one(0.17 g, 0.45 mmol) in glacial acetic acid (2 mL) and ethanol (5 mL).The reaction mixture was stirred at 0° C. for 6 h and at ambienttemperature for 18 h, diluted with ethyl acetate, washed with water andbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated in vacuo. The residue was subjected to columnchromatography and eluted with ethyl acetate/hexanes (1/1) to afford6-hydroxy-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.09 g, 57%): mp 218-221° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 11.27 (s, 1H), 7.32-7.27 (m, 1H), 7.19-7.14 (m, 2H),7.03-6.98 (m, 1H), 6.86 (d, J=6.0 Hz, 1H), 4.86-4.75 (m, 2H), 4.17-4.11(m, 1H), 3.80-3.54 (m, 4H), 1.97-1.53 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆)δ 176.8, 165.5, 163.2, 143.4, 131.6, 129.4, 128.1, 123.9, 122.4, 122.3,117.4, 110.3, 98.1, 92.0, 81.0, 76.1, 67.6, 56.4, 29.1, 25.5; MS (ES+)m/z 363.0 (M+1).

EXAMPLE 45.1 Synthesis of6-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile

Following the procedure as described in EXAMPLE 45 and makingnon-critical variations using3-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-oneto replace3-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one,6-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrilewas obtained (38%): mp 122-124° C. (ethyl acetate); ¹H NMR (300 MHz,DMSO-d₆) δ 11.30 (s, 1H), 7.81-7.78 (m, 1H), 7.62-7.47 (m, 2H),7.30-7.23 (m, 3H), 7.18 (s, 1H), 7.08-7.03 (m, 1H), 6.73-6.70 (m, 1H),6.53 (s, 1H), 5.11-4.83 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 178.8,165.7, 162.1, 141.6, 132.9, 132.7, 131.0, 129.8, 128.1, 127.7, 126.7,124.7, 124.1, 120.9, 116.7, 110.0, 99.0, 93.2, 81.1, 57.2, 41.0; MS(ES−) m/z 435.1 (M−1).

EXAMPLE 46 Synthesis of1′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one

To a stirred solution of6-fluoro-2′-oxo-1′-[2-((trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile(0.44 g, 1.0 mmol) in 1,2-dimethoxyethane (20 mL) was added hydrazinemonohydrate (1.0 mL, 21 mmol). The reaction mixture was stirred atreflux for 19 h and concentrated in vacuo. The residue was dissolved inethanol (20 mL) and isoamyl nitrite (1.50 mL, 10.7 mmol), andhypophosphorous acid (2.0 mL, 18 mmol) was added. The reaction mixturewas allowed to stir at ambient temperature for 18 h, neutralized withsaturated aqueous sodium bicarbonate and extracted with ethyl acetate(3×100 mL). The combined organic extracts was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was subjected to column chromatography and eluted with ethylacetate/hexanes (1/1) to afford1′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one(0.04 g, 10%): mp 124-126° C. (ethyl acetate/hexanes); ¹H NMR (300 MHz,DMSO-d₆) δ 12.83 (s, 1H), 7.83-7.0 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.49(m, 1H), 7.27-7.18 (m, 4H), 7.08-7.03 (m, 1H), 6.95-6.94 (m, 1H),6.81-6.77 (m, 1H), 5.07-4.83 (m, 4H); MS (ES−) m/z 436.2 (M−1).

EXAMPLE 46.1 Synthesis of1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one

Following the procedure as described in EXAMPLE 46 and makingnon-critical variations using6-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile,1′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-onewas obtained (33%): mp 117-119° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, CDCl₃) δ 10.21 (br s, 1H), 8.60-7.59 (m, 1H), 7.79 (s, 1H),7.70-7.65 (m, 1H), 7.31-6.89 (m, 7H), 5.24-4.77 (m, 4H); ¹³C NMR (75MHz, CDCl₃) δ 177.5, 160.7, 155.4, 149.6, 142.3, 141.7, 137.1, 134.9,132.3, 129.0, 126.3, 123.7, 123.6, 122.8, 121.7, 119.1, 115.6, 109.7,89.6, 80.6, 57.3, 46.1; MS (ES+) m/z 369.2 (M+1).

EXAMPLE 46.2 Synthesis of1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one

Following the procedure as described in EXAMPLE 46 and makingnon-critical variations using6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrileto replace6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile,1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-onewas obtained (47%): mp 152-154° C. (ethyl acetate/hexanes); ¹H NMR (300MHz, DMSO-d₆) δ 12.79 (br s, 1H), 8.80 (d, J=6.0 Hz, 1H), 8.24-8.21 (m,1H), 7.87 (s, 1H), 7.57-7.53 (m, 1H), 7.26-7.17 (m, 3H), 7.02-6.89 (m,3H), 5.25 (ABq, 2H), 4.87 (ABq, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 172.5,160.1, 153.2, 152.9, 143.5, 141.6, 135.5, 135.4, 134.1, 132.7, 129.1,126.7, 124.0, 123.6, 123.2, 122.5, 119.1, 116.0, 109.5, 89.4, 80.0,56.9, 42.4; MS (ES+) m/z 436.9 (M+1).

BIOLOGICAL ASSAYS

Various techniques are known in the art for testing the activity of thecompound of the invention or determining their solubility in knownpharmaceutically acceptable excipients. In order that the inventiondescribed herein may be more fully understood, the following biologicalassays are set forth. It should be understood that these examples arefor illustrative purposes only and are not to be construed as limitingthis invention in any manner.

Biological Example 1 Guanidine Influx Assay (In Vitro Assay)

This example describes an in vitro assay for testing and profiling testagents against human or rat sodium channels stably expressed in cells ofeither an endogenous or recombinant origin. The assay is also useful fordetermining the IC₅₀ of a sodium channel blocking compound. The assay isbased on the guanidine flux assay described by Reddy, N. L., et al., J.Med. Chem. (1998), 41(17):3298-302.

The guanidine influx assay is a radiotracer flux assay used to determineion flux activity of sodium channels in a high-throughputmicroplate-based format. The assay uses ¹⁴C-guanidine hydrochloride incombination with various known sodium channel modulators, to assay thepotency of test agents. Potency is determined by an IC₅₀ calculation.Selectivity is determined by comparing potency of the compound for thechannel of interest to its potency against other sodium channels (alsocalled ‘selectivity profiling’).

Each of the test agents is assayed against cells that express thechannels of interest. Voltage gated sodium channels are either TTXsensitive or insensitive. This property is useful when evaluating theactivities of a channel of interest when it resides in a mixedpopulation with other sodium channels. The following Table 1 summarizescell lines useful in screening for a certain channel activity in thepresence or absence of TTX.

TABLE 1 CELL LINE mRNA Expression Functional Characterization CHO-K1(Chinese Na_(v)1.4 expression has been The 18- to 20-fold increase inHamster Ovary; shown by RT-PCR [¹⁴C] guanidine influx was recommended Noother Na_(v) expression has completely blocked using TTX. host cellline) been detected (Na_(v)1.4 is a TTX sensitive ATTC accessionchannel) number CCL-61 L6 (rat myoblast Expression of Na_(v)1.4 and 1.5The 10- to 15-fold increase in cell) ATTC [¹⁴C] guanidine influx wasonly Number CRL-1458 partially blocked by TTX at 100 nM (Na_(v)1.5 isTTX resistant) SH-SY5Y (Human Published Expression of The 10- to 16-foldincrease in neuroblastoma) Na_(v)1.9 and Na_(v)1.7 (Blum et [¹⁴C]guanidine influx above ATTC Number al.) background was partially blockedCRL-2266 by TTX (Na_(v)1.9 is TTX resistant) SK-N-BE2C (a Expression ofNa_(v)1.8 Stimulation of BE2C cells with human pyrethroids results in a6-fold neuroblastoma cell increase in [¹⁴C] guanidine influx line ATCCNumber above background. CRL-2268) TTX partially blocked influx(Na_(v)1.8 is TTX resistant) PC12 (rat Expression of Na_(v)1.2 The 8- to12-fold increase in [¹⁴C] pheochromocytoma) expression guanidine influxwas completely ATTC Number blocked using TTX. (Na_(v)1.2 is a CRL-1721TTX sensitive channel)

It is also possible to employ recombinant cells expressing these sodiumchannels. Cloning and propagation of recombinant cells are known tothose skilled in the art (see, for example, Klugbauer, N, et al., EMBOJ. (1995), 14(6):1084-90; and Lossin, C., et al., Neuron (2002), 34, pp.877-884).

Cells expressing the channel of interest are grown according to thesupplier or in the case of a recombinant cell in the presence ofselective growth media such as G418 (Gibco/Invitrogen). The cells aredisassociated from the culture dishes with an enzymatic solution (Ix)Trypsin/EDTA (Gibco/Invitrogen) and analyzed for density and viabilityusing haemocytometer (Neubauer). Disassociated cells are washed andresuspended in their culture media then plated into Scintiplates(Beckman Coulter Inc.) (approximately 100,000 cells/well) and incubatedat 37° C./5% CO₂ for 20-24 hours. After an extensive wash with Lowsodium HEPES-buffered saline solution (LNHBSS) (150 mM Choline Chloride,20 nM HEPES (Sigma), 1 mM Calcium Chloride, 5 mM Potassium Chloride, 1mM Magnesium Chloride, 10 mM Glucose) agents diluted with LNHBSS areadded to each well. (Varying concentrations of test agent may be used).The activation/radiolabel mixture contains aconitine (Sigma) to increasethe percentage of time that the sodium channels are open, and¹⁴C-guanidine hydrochloride (ARC) to measure flux through thevoltage-gated sodium channels.

After loading the cells with test agent and activation/radiolabelmixture, the Scintiplates are incubated at ambient temperature.Following the incubation, the Scintplates are extensively washed withLNHBSS supplemented with guanidine (Sigma). The Scintiplates are driedand then counted using a Wallac MicroBeta TriLux (Perkin-Elmer LifeSciences). The ability of the test agent to block sodium channelactivity is determined by comparing the amount of ¹⁴C-guanidine presentinside the cells expressing the different sodium channels. Based on thisdata, a variety of calculations, as set out elsewhere in thisspecification, may be used to determine whether a test agent isselective for a particular sodium channel.

The IC₅₀ value of a test agent for a specific sodium channel may bedetermined using the above general method. The IC₅₀ may be determinedusing a 3, 8, 10, 12 or 16 point curve in duplicate or triplicate with astarting concentration of 1, 5 or 10 μM diluted serially with a finalconcentration reaching the sub-nanomolar, nanomolar and low micromolarranges. Typically the mid-point concentration of test agent is set at 1μM, and sequential concentrations of half dilutions greater or smallerare applied (e.g. 0.5 μM; 5 μM and 0.25 μM; 10 μM and 0.125 μM; 20 μMetc.). The IC₅₀ curve is calculated using the 4 Parameter Logistic Modelor Sigmoidal Dose-Response Model formula (fit=(A+((B−A)/(1+((C/x)^D)))).

The fold selectivity, factor of selectivity or multiple of selectivity,is calculated by dividing the IC₅₀ value of the test sodium channel bythe reference sodium channel, for example, Na_(v)1.5.

Representative compounds of the invention, when tested in the aboveassay using a known cell line that expresses a sodium channel,demonstrated an IC₅₀ (nM) activity level as set forth below in Table 2wherein “A” refers to an IC₅₀ activity level of from 1 nM to 100 nM, “B”refers to an IC₅₀ activity level from 100 nM to 1 μM, “C” refers to anIC₅₀ activity level from 1 μM to 10 μM, and “D” refers to an IC₅₀activity level equal to or greater than 10 μM. The Example numbersprovided in Table 2 correspond to the Examples herein:

TABLE 2 Ex. No. Compound Name IC₅₀ 1 2-methylspiro[furo[23-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one C 1.11′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.21′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.31′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1.45-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 1.57′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one A 1.61′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1.71′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1.91′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one1.10 (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- C2′(1′H)-one 1.10(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- A2′(1′H)-one 1.11(R)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′- Cindolin]-2′-one 1.11(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- A2′(1′H)-one 1.12 (8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-A dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one1.13 (8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 1.141′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1, A4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.151′-{[5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3- Cyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one1.16 1′-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one1.17 1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 2.31′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′- Cindol]-2′(1′H)-one 2.6 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 2.91′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]- C2′(1′H)-one 2.11 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.141′-(diphenylmethyl)-2-methylspiro[furo[2,3- Df][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one 2.161′-(diphenylmethyl)-3-methylspiro[furo[2,3- Df][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione 2.226-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H- Cspiro[benzofuran-3,3′-indolin]-2′-one 2.235-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H- Bspiro[benzofuran-3,3′-indolin]-2′-one 2.246′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6- Ab][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one 2.256-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro- B2′H-spiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5-b]furan]-7(6H)-one 2.266-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H- Cspiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5- b]furan]-7(6H)-one2.27 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro- B2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one 2.281-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Bdihydro-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′- indol]-2′(1′H)-onehydrochloride 2.291-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro- B1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]- 2′(1′H)-onehydrochloride 2.304-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro- C2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]- 2′(1′H)-one 2.311′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2- Cg][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one 2.342,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one2.35 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Cyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one2.36 2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2- Cyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one2.38 3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one 2.396-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Cbenzofuran-3,3′-indole]-5-carbonitrile 2.406-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Cbenzofuran-3,3′-indole]-5-carbonitrile 2.411′-(4-methoxybenzyl)-3-methylspiro[furo[2,3- Cf][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one 2.441′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.451′-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.495′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.502′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile 2.611′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′- Dindol]-2′(1′H)-one 2.634′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 2.644′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 2.656-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4- Cdioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]- 7(6H)-one 2.666′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 36-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)- C one 3.14′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-2′(1′H)-one 3.2 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-oneC 3.3 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.45′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-2′(1′H)-one 3.56′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-2′(1H)-one 3.63-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]- B 2′(1′H)-one3.7 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one C 3.85-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one C 3.102,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- A 2′(1′H)-one3.11 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′- Cindol]-2′(1′H)-one 3.122-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)- D one3.13 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]- C2,2′(1′H,3H)-dione 3.141-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]- C2,2′(1H,1′H)-dione 3.157′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-2′(1′H)-one 3.167′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-2′(1′H)-one 3.174′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 3.216,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)- B one 3.221-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]- C2,2′(1′H,3H)-dione 3.234-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′- Cindoline]-2′,3(2H)-dione 3.242,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]- C 2′(1′H)-one3.25 (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]- C2′(1′H)-one 3.26 (3R)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-C 2′(1′H)-one 3.282′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′- C[1,4]dioxino[2,3-f]indol]-7′(6′H)-one 3.296-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′- Cindole]-5-carbonitrile 3.306-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]- C5-carbonitrile 3.324′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-2′(1′H)-one 3.334′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 3.34 4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 3.354′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 3.40spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1H)-one 5,5′- C dioxide3.41 spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one C3.42 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′- Cindol]-2′(1′H)-one 3.445,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one C 3.455′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]- C2(1H)-one 3.466-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)- C one 3.475-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)- C one 3.482,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]- C 2′(1′H)-one3.49 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′- C[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one 3.504′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 3.51spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one C 41′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.21′-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.31′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.41′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.51′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.61′-(tetrahydro-2H-pyran-4-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.7methyl 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxylate 4.81′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.91′-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.101′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.11methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4- carboxylate4.12 1′-(2-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.131′-(4-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.141′-benzyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-2′(1′H)-one 4.151′-(biphenyl-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.161′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.171′-[(3-bromoisoxazol-5-yl)methyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.181′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.201′-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 4.211′-[(1-ethyl-1H-imidazol-5-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.223-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]benzonitrile 4.234-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′- Aindoline]-1′-yl)methyl)benzonitrile 4.244′-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrile 4.251′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.261′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.271′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.281′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.291′-[(4-benzylmorpholin-2-yl)methyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.334′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.344′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.354′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.361′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.371′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.381′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.391′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.411′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.431′-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.441′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.451′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.461′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.471′-(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.481′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.49(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.50(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.51(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.521′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.531′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H- Bspiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one 4.541′-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H- Bspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]- 2′(1′H)-one 4.551′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3- Bh][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 4.562-methyl-1′-(3-methylbutyl)spiro[furo[2,3- Cf][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one 4.572-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3- Cf][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one 4.582-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3- Cf][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one 4.591-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H- Cspiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]- 2,2′(1′H,3H)-dione 4.601-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Cf][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione 4.616-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.626-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 4.636-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2- Cylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.645-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-2- Bylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.655-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 4.665-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.671′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]- B2′(1′H)-one 4.68 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-B benzofuran-3,3′-indol]-2′(1′H)-one 4.701′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7- Ctetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]- 2′(1′H)-one 4.721′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3- Cf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.73(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Ayl)acetonitrile 4.74 7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2- Bfuryl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one4.75 1′-[(5-chloro-2-thienyl)methyl]-7′- B(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.761′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′- B(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.771′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.78 tert-butyl[1-cyclopropyl-3-(2′-oxospiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]carbamate 4.791′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.803-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Ayl)propanenitrile 4.811′-[(2-bromo-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.821′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one4.83 6-Fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2- Cyl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.844′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- B1′(2′H)-yl)acetonitrile 4.851′-[(2-amino-1,3-thiazol-4-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.864′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.871′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′- Adihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]- 7′-carbonitrile4.88 1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2′-oxo-1′,2′- Adihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]- 7′-carbonitrile4.89 4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.904′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.914′-chloro-1′-[(2-isopropyl-1,3-thiazol-4- Ayl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one4.92 4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3- Bthiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.933′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 4.943-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]benzonitrile 4.951′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.964-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]benzonitrile 4.971′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.981′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.991′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 4.1001′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1011′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1021′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1034′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1041′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1052′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1- Cbenzofuran-3,3′-indole]-6-carbonitrile 4.1063-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl]methyl}benzonitrile 4.107(8S)-1′-[(5-fluoropyridin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.108(8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.109(S)-1′-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6- Ab][1,4]dioxine-8,3′-indolin]-2′-one 4.1101′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1111′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′- Bdihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile 4.1121′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1131′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.114(8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.116(8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1181′-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1191′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1201′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1211′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1221′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1241′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole- A8,3′-indol]-2′(1′H)-one 4.1251′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole- C8,3′-indol]-2′(1′H)-one 4.1266-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2- Cf][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one 4.1271′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2- Cf][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one 4.1291-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′- Ctetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]- 2(1H)-one 4.1301′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]- C2′(1′H)-one 5 1′-[(2-methoxypyrimidin-5-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.17′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6- Bdihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]- 2′-one 5.2(3R)-1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-2′(1′H)-one 5.3(3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- C3,3′-indol]-2′(1′H)-one 5.4(3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 5.5(3R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.6(3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 5.7(3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.83-methyl-1′-{[5-(trifluoromethyl)furan-2- Cyl]methyl}spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione 5.131′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.151′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.16(8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.17(8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.18(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.196-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4- Cdioxino[2,3-f]indole-8,3′-indole′-2′,7(1′H,6H)-dione 5.204′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.211′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.221′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 5.231′-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.259-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.269-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.279-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.281′-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3- Ag]chromene-3,3′-indol]-2′(1′H)-one 5.291′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H- Bspiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one 5.311-(pyridin-2-ylmethyl)spiro[indole-3,3′-thieno[2,3- Cf][1]benzofuran]-2(1H)-one 5,5′-dioxide 5.321′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.331′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.346-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 5.355-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 5.361′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1, B4]benzodioxine-7,3′-indol]-2′(1′H)-one 5.371′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]- 2′(1′H)-one 5.386-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- C1′(2′H)-yl)methyl]pyrimidine-2,4(1H,3H)-dione 61′-[(5-Chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.14′-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3- Ayl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one6.2 5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 6.31′-[(3-chlorothiophen-2-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.41′-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4- Cyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one6.5 1′-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4- Byl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one6.6 1′-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.71′-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one6.8 1′-([1,3]oxazolo[4,5-b]pyridin-2-ylmethyl)spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 7.11′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.2 methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]furan-2-carboxylate7.10 1′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.111′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.121′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.131′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.141′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.15(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.16N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-1′-(2′H)- yl)methyl]benzenesulfonamide7.17 1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.181′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.191′-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.201′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.211′-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.221′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.231′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.241′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.251′-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.261′-[(2-fluoro-5-trifluoromethyl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.271′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.281′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 81′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 8.17′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.27′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.34′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.41′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 8.5 (8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.6(8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.7(8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.8(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.91′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7- Bdihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.101′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2- Bb:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one 8.111′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H- Cspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]- 2′(1′H)-one 8.121′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H- Bspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]- 2′(1′H)-one 8.143-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H- Cspiro[benzofuro[6,5-d]oxazole-7,3′-indoline]- 2,2′(3H,6H)-dione 8.157′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H- Aspiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one 8.167′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7- Adihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′- indolin]-2′-one 8.173′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 8.181′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 8.19(8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 93-methyl-1′-{[5-(trifluoromethyl)furan-2- Ayl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′- indol]-2′(1′H)-one9.1 1′-[2-(2-methoxyethoxy)ethyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 9.21′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.31′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.41′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.51′-(pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.61′-(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.71′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.81′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.91′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.101′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.111′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.121′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.131′-(2H-benzotriazol-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 9.14 methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.15 methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.16 methyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.171′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.185′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.196′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.201′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.212-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3- Cf][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one 9.221′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2- Cmethylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]- 2′(1′H)-one 9.234-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7- Adihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′- indoline]-2′,3(2H)-dione9.24 3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.253-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.263-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.275,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 9.285,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′- Bindol]-2′(1′H)-one 9.29 5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4- Cylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 9.305-fluoro-6-methoxy-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 9.315,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′- Cindol]-2′(1′H)-one 9.325,6-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 9.336-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′- Aindolin]-2′-one 9.346-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′- Aindol]-2′(1′H)-one 9.356-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 9.366-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 9.371′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.381′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′-(1′H)-one 9.39(8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.40 tert-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate 9.413-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.423-methyl-1′-{[3-(trifluoromethyl)pyridin-2- Byl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′- indol]-2′(1′H)-one9.43 1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.44 ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-1′(2′H)-yl)acetate 9.451′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.466-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 9.476-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1- Cbenzofuran-3,3′-indole]-5-carbonitrile 9.486-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1- Cbenzofuran-3,3′-indole]-5-carbonitrile 9.506-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′- Cdihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 9.516-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}- C1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5- carbonitrile 9.53 methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzoate 9.541′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.553-methyl-1′-(3-methylbutyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.563-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.571′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.58 methyl2-[(3-methyl-2′-oxospiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate 9.59 methyl 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-A g][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzoate 9.601′-[(4-benzylmorpholin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.645,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′- Bindol]-2′(1′H)-one 9.655,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 9.662-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione 9.671′-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2- Be][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one 9.70(8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.716′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 9.726′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 9.734′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.744′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.756-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 9.765-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 101-(pyridazin-4-ylmethy)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indo]-2′(1′H)-one 111′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.11′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.21′-[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.31′-[(2-piperidin-1-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.41′-[(2-methoxy-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.51′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-2′(1′H)-one 11.61′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.81′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.101′-[(1-methylpiperidin-4-yl)methyl]-5,6- Ddihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.123-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-1′(2′H)-yl)methyl]benzoic acid 11.131′-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.141′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.151′-[(5-pyridin-4-ylfuran-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.161′-(4-pyridin-3-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.171′-[(2′-fluorobiphenyl-4-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.181′-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Ayl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.19 4′-chloro-1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.20 4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3- Ayl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.21 4′-chloro-1′-{1-[5-(difluoromethyl)-1,2,4-oxadiazol-3- Ayl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.22 1′-{[5-(difluoromethyl)-1,2,4-oxadiazol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.23 1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.241′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.254′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.26 1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.27 1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.281′-{3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.291′-[4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.302-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-1′(2′H)-yl)methyl]benzoic acid 11.314-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]benzoic acid 11.325-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Cindol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid 11.33N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]furan-2-carboxamide11.34 1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.352′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6- Btetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- indole]-4′-carbonitrile11.37 4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.384′-(pyrrolidin-1-ylmethyl)-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.394′-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.411′-[(4-methylmorpholin-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.421′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.431′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-2′(1′H)-one 11.441′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.451′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.461′-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.476-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 11.48N-{2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′- Cdihydrospiro[1-benzofuran-3,3′-indol]-6- yl}methanesulfonamide 11.496-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]- A2′(1′H)-one 11.506-hydroxy-1′-(3-methylbutyl)-5-(trifluoroacetyl)spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one 11.526-[(3R)-pyrrolidin-3-ylamino]-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 11.536-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 11.546-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 11.566-[(3S)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 11.586-[(3R)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 11.601′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione 11.611′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-2′(1′H)-one 11.62N-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxamide 11.631′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrogen chloride 11.64(3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1- Ayl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride11.65 (3R)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1- Byl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride11.66 (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.67(3R)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.68(3R)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.69(3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2″(1′H)-one 11.701′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.711′-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3- Cf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.721′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one11.73 N-isopropyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxamide 11.745-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- A1′(2′H)-yl)methyl]thiophene-3-carbonitrile 11.752′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindole]-7′-carbonitrile 11.783′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 11.793′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]- 2′(3′H)-one 11.802-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine- 3-carbonitrile11.81 (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.831′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.841′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.856-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2- Bylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 11.863-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Cindol]-1′(2′H)-yl)methyl]benzoic acid 11.874-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Cindol]-1′(2′H)-yl)methyl]benzoic acid 11.901′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.921′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.94N-{3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)- yl)methyl]phenyl}methanesulfonamide 11.951′-[(1-oxydopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.971′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrobromide 11.98N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3- yl}methanesulfonamide 11.991′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride 11.1001′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-onehydrochloride 11.1011′-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride 11.1021′-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.1031′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.104 1′-[(4-methylmorpholin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.106 (8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.107 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2- Ce][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one 11.1086-chloro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Cdihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]- 2′(1′H)-one11.109 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Cdihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]- 2′(1′H)-one11.110 1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.111 5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′- Aindol]-2′(1′H)-one hydrochloride 11.1125,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 12N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.1N-(2-methoxyethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.2N-hexyl-N-methyl-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.3N-(2-ethylbutyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.4N-(2,4-dimethylphenyl)-3-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.53-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(2- phenylpropyl)benzamide 12.6N-[(1S)-1-cyclohexylethyl]-3-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.7N-[(1R)-1-cyclohexylethyl]-3-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.8N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Db:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.9N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.10N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.11N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.12N-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.13N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.14N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.15N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.16N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.171′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 12.18N-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.19N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.20N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.21 N-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-C dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.22N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.23N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.24N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.25N-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.264-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-1′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)phenyl]benzamide 12.274-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-phenylbenzamide 12.28N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.29N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.304-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2- ylethyl)benzamide 12.314-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]benzamide 12.32N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.331′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 12.34N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.35N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.36N-(3-fiuorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.37N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.384-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(thiophen-2- ylmethyl)benzamide 12.39N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.40N-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.41N-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.42N-cyclobutyl-4-[(2-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3-indol]-1(2H)-yl)methyl]benzamide 12.434-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide 12.44N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.45N-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Cb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.462-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-1′(2′H)-yl)acetamide 12.47N-(4-ethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Cb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.48N,N-diethyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.49N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.50N-[3-(1-methylethoxy)propyl]-2-(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.512-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)-N-propylacetamide 12.52N-methyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)-N-phenylacetamide 12.53N-(2,5-dimethylphenyl)-2-(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.54 N-(2,4-dimethylphenyl)-2-(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.55 N-(2,3-dimethylphenyl)-2-(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.56 N-(2,6-dimethylphenyl)-2-(2′-oxo-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.57N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3- carboxamide 12.585-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- A1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3- carboxamide 12.59N,N-dimethyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan- 3-carboxamide12.60 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]benzamide 12.613-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]benzamide 12.62N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.63N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide 12.64N-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide dihydrochloride 12.65N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzamide 135-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Cindol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid 13.1N,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxamide 13.2N-methyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxamide 13.32-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide 13.4N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4- carboxamide13.5 N-cyclopropyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- A7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4- carboxamide 13.6N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide 13.7N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide 13.11N-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)propyl]-2- (trifluoromethoxy)benzamide 141′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 14.11′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 14.21′-{(2S)-2-[(4-fluorobenzyl)oxy]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 14.31′-[(2S)-2-(pyridin-2-ylmethoxy)propyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 14.41′-(3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 14.51′-(4,4,4-trifluoro-3-hydroxybutyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 15.11′-{3-[(3-methylbutyl)amino]propyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-onehydrochloride 15.2 1′-{3-[butyl(methyl)amino]propyl}-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-onehydrochloride 15.3 1′-{3-[(2,2,2-trifluoroethyl)amino]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-onehydrochloride 15.43-{[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)propyl]amino}propanenitrile hydrochloride 164′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.14′-[(E)-2-(4-fluorophenyl)ethenyl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.24′-dibenzo[b,d]thiophen-4-yl-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.34′-(1-benzothiophen-3-yl)-1′-[(2R)-tetrahydrofuran-2- Cylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.44′-(1-methyl-1H-indol-5-yl)-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.54′-[3,5-bis(trifluoromethyl)phenyl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.64′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- B5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- indol]-2′(1′H)-one16.7 4′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.84′-(4-butoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.94′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- A5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- indol]-2′(1′H)-one16.10 4′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Cdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.114′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5- B(trifluoromethyl)furan-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.121′-[(5-chloro-2-thienyl)methyl]-4′-[6-(dimethylamino)pyridin- B3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one 16.131′-[(5-chloro-2-thienyl)methyl]-4′-(3-furyl)spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.144′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3- Cf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.594′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7- Bdihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′- indolin]-2′-one16.60 4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H- Aspiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one 16.61(7S)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole- A7,3′-indol]-2′(1′H)-one 16.62(7R)-4′-furan-3-yl-1′-methylspiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.881′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3- Cyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 171′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 17.11′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 17.21′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 18 ethyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indole]-1′(2′H)-carboxylate 18.1 tert-butyl4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole- A7,3′-indole]-1′(2′H)-carboxylate 18.2 tert-butyl2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate 191′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro- C3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- indol]-2′(1′H)-one20 6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3- Cg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D- galactopyranose 211′-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-2′(1′H)-one 221′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 23 1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-A dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 281′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 29.11′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3- Bmethylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]- 2′(1′H)-onehydrochloride 29.2 1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-onehydrochloride 30 1′-[4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 312′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3- Btetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide 32 1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3-A dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one32.1 1′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 32.21′-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 33.25,6-difluoro-1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[1- Cbenzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 33.31′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 33.41′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 351′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 35.11′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3- Cdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 361′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 371′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 38N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide 391′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 401′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 416-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrile 426-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide 443-amino-1′-(4-methoxybenzyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.13-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.23-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Cf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.33-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2- Cf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 456-hydroxy-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′- Cdihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 45.16-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′- Cdihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 461′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole- C5,3′-indol]-2′(1′H)-one 46.11′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′- Bindol]-2′(1′H)-one 46.21′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6- Bdihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one

Biological Example 2 Electrophysiological Assay (In Vitro Assay)

Cells expressing the channel of interest are cultured in DMEM growthmedia (Gibco) with 0.5 mg/mL G418, +/−1% PSG, and 10% heat-inactivatedfetal bovine serum at 37° C. and 5% CO₂. For electrophysiologicalrecordings, cells are plated on 10 mm dishes.

Whole cell recordings are examined by established methods of whole cellvoltage clamp (Bean et al., op. cit.) using an Axopatch 200B amplifierand Clampex software (Axon Instruments, Union City, Calif.). Allexperiments are performed at ambient temperature. Electrodes arefire-polished to resistances of 2-4 Mohms Voltage errors and capacitanceartifacts are minimized by series resistance compensation andcapacitance compensation, respectively. Data are acquired at 40 kHz andfiltered at 5 kHz. The external (bath) solution consists of: NaCl (140mM), KCl (5 mM), CaCl₂ (2 mM), MgCl₂ (1 mM), HEPES (10 mM) at pH 7.4.The internal (pipette) solution consists of (in mM): NaCl (5), CaCl₂(0.1), MgCl₂ (2), CsCl (10), CsF (120), HEPES (10), EGTA (10), at pH7.2.

To estimate the steady-state affinity of compounds for the resting andinactivated state of the channel (K_(r) and K_(i), respectively), 12.5ms test pulses to depolarizing voltages from −60 to +90 mV from aholding potential of −120 m V is used to construct current-voltagerelationships (I-V curves). A voltage near the peak of the IV-curve (−30to 0 m V) is used as the test pulse throughout the remainder of theexperiment. Steady-state inactivation (availability) curves are thenconstructed by measuring the current activated during a 8.75 ms testpulse following 1 second conditioning pulses to potentials ranging from−120 to −10 m V.

The steady-state voltage-dependence of binding of a compound to a sodiumchannel is determined by measuring the blockage of the ionic current attwo holding potentials. Binding to rested-state channels is determinedby using a holding potential of −120 mV, so that maximal availability isachieved. Binding to inactivated-state channels is evaluated at aholding potential such that only 10% of the channels are available toopen. The membrane potential is held at this voltage for at least 10seconds so that drug binding can equilibrate.

The apparent dissociation constant at each voltage is calculated withthe equation:

${\%\mspace{14mu}{inhibition}} = \frac{\lbrack{Drug}\rbrack}{\left( {\lbrack{Drug}\rbrack + K_{d}} \right)}$where K_(d) is the dissociation constant (either K_(r) or K_(i)), and[Drug] is the concentration of the test compound.

Representative compounds of the invention, when tested in this model,demonstrated affinities for the inactivated state of the channel ofinterest as set forth below in Table 3 wherein “A” refers to K_(i) ofless than 300 nM and “B” refers to K_(i) of greater than 300 nM. TheExample numbers provided in Table 3 correspond to the Examples herein:

TABLE 3 Ex. No. Compound Name K_(i) (μM) 1.21′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.10(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)- Aone 1.11 (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-B 2′(1′H)-one 1.12(8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 1.13(8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 2.276-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro- A2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one 2.342,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one2.35 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one2.54 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8- Bdihyrdospiro[1,4-dioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1′H)-one 2.656-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4- Bdioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]- 7(6H)-one 36-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.296-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′- Bindole]-5-carbonitrile 3.334′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 3.344′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-2′(1′H)-one 3.354′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 3.41spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one B 41′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.31′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.61′-(tetrahydro-2H-pyran-4-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.81′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 4.101′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.161′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.201′-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 4.223-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]benzonitrile 4.223-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]benzonitrile 4.271′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.281′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.291′-[(4-benzylmorpholin-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.361′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.381′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.431′-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.451′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.481′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.49(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.50(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.51(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.541′-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H- Aspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]- 2′(1′H)-one 4.551′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3- Bh][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 4.686-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 4.1034′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.17′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6- Adihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]- 2′-one 5.4(3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 5.5(3R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.6(3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 5.7(3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.17(8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.18(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.4(R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-2′(1′H)-one 7.81′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.15(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.41′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 8.6 (8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.7(8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.8(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 8.121′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3- Bh][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 93-methyl-1′-{[5-(trifluoromethyl)furan-2- Ayl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′- indol]-2′(1′H)-one9.6 1′-(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.201′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.234-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2H- Bspiro[furo[2,3-g][1,4]benzoxazine-8,3′-indole]- 2′,3(1′H,4H)-dione 9.243-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 10.11′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.141′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.271′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.33N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan- 2-carboxamide11.64 (3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1- Byl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride11.66 (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.67(3R)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.69(3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2″(1′H)-one 11.856-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2- Bylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 164′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.64′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- A5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one16.7 4′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2- Aylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.94′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- A5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one16.10 4′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.801′-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one

Biological Example 3 Analgesia Induced by Sodium Channel Blockers

Heat Induced Tail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention can be observed through heat-induced tail-flick inmice. The test includes a heat source consisting of a projector lampwith a light beam focused and directed to a point on the tail of a mousebeing tested. The tail-flick latencies, which are assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, are measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals undergo assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals are then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/Kg are administered intramuscularly. Following doseadministration, the animals are closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound is determined via regression analysis. The analgesic activityof the test compounds is expressed as a percentage of the maximumpossible effect (% MPE) and is calculated using the following formula:

${\%\mspace{14mu}{MPE}} = {\frac{{{Postdrug}\mspace{14mu}{latency}} - {{Predrug}\mspace{14mu}{latency}}}{{{Cut}\text{-}{off}\mspace{14mu}{time}\mspace{14mu}\left( {10\mspace{14mu} s} \right)} - {{Predrug}\mspace{14mu}{latency}}} \times 100\%}$

where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals are briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals are randomly injected with the test articles. At 30 minutesafter drug administration, 50 μL of 10% formalin is injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition begins immediately after formalinadministration, for duration of 90 minutes.

The images are captured using the Actimetrix Limelight software whichstores files under the *.llii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis isconducted by watching the animal behaviour and scoring each according totype, and defining the length of the behaviour (Dubuisson and Dennis,1977). Scored behaviours include: (1) normal behaviour, (2) putting noweight on the paw, (3) raising the paw, (4) licking/biting or scratchingthe paw. Elevation, favoring, or excessive licking, biting andscratching of the injected paw indicate a pain response. Analgesicresponse or protection from compounds is indicated if both paws areresting on the floor with no obvious favoring, excessive licking, bitingor scratching of the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (% MPIE) and (2) pain score.The % MPIEs is calculated by a series of steps, where the first is tosum the length of non-normal behaviours (behaviours 1,2,3) of eachanimal. A single value for the vehicle group is obtained by averagingall scores within the vehicle treatment group. The following calculationyields the MPIE value for each animal:MPIE(%)=100−[(treatment sum/average vehicle value)×100%]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia is assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 μL of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) is injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals are allowedto recover from the anaesthesia and the baseline thermal and mechanicalnociceptive thresholds of all animals are assessed one week after theadministration of CFA. All animals are habituated to the experimentalequipment for 20 minutes on the day prior to the start of theexperiment. The test and control articles are administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used are previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Animals are placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals are allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 45 respectively, and a cut off time of 20seconds is employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals areplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs areapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force is used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animals areanaesthetized under 3.5% isofluorane, which is delivered via a nosecone, a 1 cm longitudinal incision is made using a number 10 scalpelblade in the plantar aspect of the left hind paw through the skin andfascia, starting 0.5 cm from the proximal edge of the heel and extendingtowards the toes. Following the incision, the skin is apposed using 2,3-0 sterilized silk sutures. The injured site is covered with Polysporinand Betadine. Animals are returned to their home cage for overnightrecovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals are placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs are appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continuesuntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Neuropathic pain model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision is made through the skin and thefascia at the mid thigh level of the animals' left hind leg using a no.10 scalpel blade. The left sciatic nerve is exposed via blunt dissectionthrough the biceps femoris with care to minimize haemorrhagia. Fourloose ligatures are tied along the sciatic nerve using 4-0non-degradable sterilized silk sutures at intervals of 1 to 2 mm apart.The tension of the loose ligatures is tight enough to induce slightconstriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve is exposed without further manipulation.Antibacterial ointment is applied directly into the wound, and themuscle is closed using sterilized sutures. Betadine is applied onto themuscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs are applied perpendicularly to the plantarsurface of both paws of the animals in an ascending order starting fromthe 0.1 g hair, with sufficient force to cause slight buckling of thehair against the paw. Testing continues until the hair with the lowestforce to induce a rapid flicking of the paw is determined or when thecut off force of approximately 20 g is reached. This cut off force isused because it represents approximately 10% of the animals' body weightand it serves to prevent raising of the entire limb due to the use ofstiffer hairs, which would change the nature of the stimulus.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Following the measurement of tactile thresholds,animals are placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26°C. for all test trials. Animals are allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 55 respectively, and a cut off time of 20seconds is used to prevent tissue damage.

Neuropathic Pain Model: Spinal Nerve Ligation

The spinal nerve ligation (SNL) neuropathic pain model is used as ananimal (i.e. rat) model of neuropathic pain. In the SNL test, the lumbarroots of spinal nerves L5 and L6 are tightly ligated to cause nerveinjury, which results in the development of mechanical hyperalgesia,mechanical allodynia and thermal hypersensitivity. The surgery isperformed two weeks before the test day in order for the pain state tofully develop in the animals. Several spinal nerve ligation variationsare used to characterize the analgesic properties of a compound of theinvention.

-   -   (1) Ligation of the L5 spinal nerve;    -   (2) Ligation of the L5 and L6 spinal nerves;    -   (3) Ligation and transection of the L5 spinal nerve;    -   (4) Ligation and transection of the L5 and L6 spinal nerves; or    -   (5) Mild irritation of the L4 spinal nerve in combination with        any one of the above (1)-(4).

While the animals are anaesthetized under 3.5% isofluorane delivered viaa nose cone, an approximately 2.5 cm longitudinal incision is made usinga number 10 scalpel blade in the skin just lateral to the dorsalmidline, using the level of the posterior iliac crests as the midpointof the incision. Following the incision, the isoflourane is readjustedto maintenance levels (1.5%−2.5%). At mid-sacral region, an incision ismade with the scalpel blade, sliding the blade along the side of thevertebral column (in the saggital plane) until the blade hits thesacrum. Scissors tips are introduced through the incision and the muscleand ligaments are removed from the spine to expose 2-3 cm of thevertebral column. The muscle and fascia are cleared from the spinalvertebra in order to locate the point where the nerve exits from thevertebra. A small glass hook is placed medial to the spinal nerves andthe spinal nerves are gently elevated from the surrounding tissues. Oncethe spinal nerves have been isolated, a small length of non-degradable6-0 sterilized silk thread is wound twice around the ball at the tip ofthe glass hook and passed back under the nerve. The spinal nerves arethen firmly ligated by tying a knot, ensuring that the nerve bulges onboth sides of the ligature. The procedure may be repeated as needed. Insome animals, the L4 spinal nerve may be lightly rubbed (up to 20 times)with the small glass hook to maximize the development of neuropathicpain. Antibacterial ointment is applied directly into the incision, andthe muscle is closed using sterilized sutures. Betadine is applied ontothe muscle and its surroundings, followed by skin closure with surgicalstaples or sterile non-absorbable monofilament 5-0 nylon sutures.

The analgesic effect produced by topical administration of a compound ofthe invention to the animals can then be observed by measuring the pawwithdrawal threshold of animals to mechanical tactile stimuli. These maybe measured using either the mechanical allodynia procedure or themechanical hyperalgesia procedure as described below. Afterestablishment of the appropriate baseline measurements by either method,topical formulation of a compound of the invention is applied on theipsilateral ankle and foot. The animals are then placed in plastictunnels for 15 minutes to prevent them from licking the treated area andremoving the compound. Animals are placed in the acrylic enclosure for15 minutes before testing the ipsilateral paw by either of the methodsdescribed below, and the responses are recorded at 0.5, 1.0 and 2.0 hourpost treatment.

A. Mechanical Allodynia Method

The pain threshold of animals to mechanical alloydnia for both operatedand control animals can be measured approximately 14 days post-surgeryusing manual calibrated von Frey filaments as follows. Animals areplaced in an elevated plexiglass enclosure set on a mire mesh surface.Animals are allowed to acclimate for 20-30 minutes. Pre-calibrated VonFrey hairs are applied perpendicularly to the plantar surface of theipsilateral paw of the animals starting from the 2.0 g hair, withsufficient force to cause slight buckling of the hair against the paw toestablish the baseline measurements. Stimuli are presented in aconsecutive manner, either in an ascending or descending order until thefirst change in response is noted, after which four additional reponsesare recorded for a total of six responses. The six responses measured ingrams are entered into a formula as described by Chaplan, S. R. et al.,J. Neurosci. Methods, 1994 July; 53(1):55-63, and a 50% withdrawalthreshold is calculated. This constitutes the mechanical allodyniavalue.

B. Mechanical Hyperalgesia Method

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals were placed in an elevated Plexiglasenclosure set on a wire mesh surface. After 15 minutes of accommodationin this enclosure, a von Frey hair was applied perpendicularly to theplantar surface of the ipsilateral hind paws of the animals, withsufficient force, measured in grams, to elicit a crisp response of thepaw. The response indicated a withdrawal from the painful stimulus andconstituted the efficacy endpoint. The data were expressed as percentchange from baseline threshold measured in grams.

Biological Example 4 Aconitine Induced Arrhythmia Test

The antiarrhythmic activity of compounds of the invention isdemonstrated by the following test. Arrhythmia is provoked byintravenous administration of aconitine (2.0 μg/Kg) dissolved inphysiological saline solution. Test compounds of the invention areintravenously administered 5 minutes after the administration ofaconitine. Evaluation of the anti-arrhythmic activity is conducted bymeasuring the time from the aconitine administration to the occurrenceof extrasystole (ES) and the time from the aconitine administration tothe occurrence of ventricular tachycardia (VT).

In rates under isoflurane anaesthesia (¼ to ⅓ of 2%), a tracheotomy isperformed by first creating an incision in the neck area, then isolatingthe trachea and making a 2 mm incision to insert tracheal tube 2 cm intothe trachea such that the opening of the tube is positioned just on topof the mouth. The tubing is secured with sutures and attached to aventilator for the duration of the experiment.

Incisions (2.5 cm) are then made into the femoral areas and using ablunt dissection probe, the femoral vessels are isolated. Both femoralveins are cannulated, one for pentobarbital anaesthetic maintenance(0.02-0.05 mL) and one for the infusion and injection of drug andvehicle. The femoral artery is cannulated with the blood pressure gelcatheter of the transmitter.

The ECG leads are attached to the thoracic muscle in the Lead IIposition (upper right/above heart—white lead and lower left/belowheart—red lead). The leads are secured with sutures.

All surgical areas are covered with gauze moistened with 0.9% saline.Saline (1-1.5 mL of a 0.9% solution) is supplied to moisten the areaspost-surgery. The animals' ECG and ventillation are allowed toequilibrate for at least 30 minutes.

The arrhythmia is induced with a 2 μg/Kg/min aconitine infusion for 5minutes. During this time the ECG is recorded and continuouslymonitored. Compounds of the present invention can be tested in theseassays to determine their effectiveness in treating arrhythmia.

Biological Example 5 Ischemia Induced Arrhythmia Test

Rodent models of ventricular arrhythmias, in both acute cardioversionand prevention paradigms have been employed in testing potentialtherapeutics for both atrial and ventricular arrhythmias in humans.Cardiac ischemia leading to myocardial infarction is a common cause ofmorbidity and mortality. The ability of a compound to preventischemia-induced ventricular tachycardia and fibrillation is an acceptedmodel for determining the efficacy of a compound in a clinical settingfor both atrial and ventricular tachycardia and fibrillation.

Anaesthesia is first induced by pentobarbital (i.p.), and maintained byan i.v. bolus infusion. Male SD rats have their trachea cannulated forartificial ventilation with room air at a stroke volume of 10 mL/Kg, 60strokes/minute. The right femoral artery and vein are cannulated withPE50 tubing for mean arterial blood pressure (MAP) recording andintravenous administration of compounds, respectively.

The chest is opened between the 4^(th) and 5^(th) ribs to create a 1.5cm opening such that the heart is visible. Each rat is placed on anotched platform and metal restraints are hooked onto the rib cageopening the chest cavity. A suture needle is used to penetrate theventricle just under the lifted atrium and exited the ventricle in adownward diagonal direction so that a >30% to <50% occlusion zone (OZ)would be obtained. The exit position is ˜0.5 cm below where the aortaconnects to the left ventricle. The suture is tightened such that aloose loop (occluder) is formed around a branch of the artery. The chestis then closed with the end of the occluder accessible outside of thechest.

Electrodes are placed in the Lead II position (right atrium to apex) forECG measurement as follows: one electrode inserted into the rightforepaw and the other electrode inserted into the left hind paw.

The body temperature, MAP, ECG, and heart rate are constantly recordedthroughout the experiment. Once the critical parameters has stabilized,a 1-2 minute recording is taken to establish the baseline values.Infusion of a compound of the invention or control substance isinitiated once baseline values are established. After a 5-minuteinfusion of compound or control, the suture is pulled tight to ligatethe LCA and create ischemia in the left ventricle. The criticalparameters are recorded continuously for 20 minutes after ligation,unless the MAP reached the critical level of 20-30 mmHg for at least 3minutes, in which case the recording is stopped because the animal wouldbe declared deceased and is then sacrificed. The ability of compounds ofthe invention to prevent arrhythmias and sustain near-normal MAP and HRis scored and compared to control.

Biological Example 6 In Vivo Assay for Benign Prostate Hyperplasia (BPH)

The effectiveness of the compounds of the present invention for treatingBPH can be demonstrated by the following in vivo assay.

Dogs are dosed orally with compounds of the present invention at oraldoses of between 0 mg/Kg and 100 mg/Kg for a period of 4 weeks. Acontrol group receives placebo. The animals are sacrificed and theprostate glands dissected out, dabbed dry and then weighed.

Biological Example 7 In Vivo Assay for Antihypercholesterlemia Efficacyand Antiatherosclerotic Efficacy

Dogs have cardiovascular systems similar to that of humans, making themideal for studying the effects of medicinal compounds designed to treatcardiovascular disorders.

Dogs are dosed orally at a range of 0 mg/Kg to 100 mg/Kg daily withcompounds of the present invention for a period of 2-4 weeks. After 2and 4 weeks the animals are bled and their serum collected for totalcholesterol analysis and compared to the animals dosed with vehiclealone (0 mg/Kg).

The measurement of cholesterol is one of the most common tests performedin the clinical laboratory setting. Simple fluorometric methods for thesensitive quantitation of total cholesterol in plasma or serum arecommonly used. In one assay, cholesteryl esters in the sample are firsthydrolyzed by cholesterol esterase. All cholesterol, whether previouslyesterified or existing free in the circulation, is then oxidized bycholesterol oxidase to the corresponding ketone and hydrogen peroxide.ADHP (10-acetyl-3,7-dihydroxyphenoxazine) is utilized as a highlysensitive and stable probe for hydrogen peroxide. Horseradish peroxidasecatalyzes the reaction of ADHP with hydrogen peroxide to yield thehighly fluorescent product resorufin, which can be monitored usingexcitation wavelengths of 565-580 nm and emission wavelengths of 585-595nm.

Biological Example 8 In Vivo Assay for Treatment of Pruritis

The compounds of the invention can be evaluated for their activity asantipruritic agents by in vivo test using rodent models. One establishedmodel for peripherally elicited pruritus is through the injection ofserotonin into the rostral back area (neck) in hairless rats. Prior toserotonin injections (e.g., 2 mg/mL, 50 μL), a dose of a compound of thepresent invention can be applied systemically through oral, intravenousor intraperitoneal routes or topically to a circular area fixed diameter(e.g. 18 mm). Following dosing, the serotonin injections are given inthe area of the topical dosing. After serotonin injection the animalbehaviour is monitored by video recording for 20 min-1.5 h, and thenumber of scratches in this time compared to vehicle treated animals.Thus, application of a compound of the current invention could suppressserotonin-induced scratching in rats.

Biological Example 9

Cytochrome P450 (CYP450) Inhibition Assay

CYP450 (CYP) is the designation for a superfamily of enzymes. Eachfamily consists of one or more subfamilies and each subfamily containsone or more specific CYP isoforms. The Cytochrome P450 (CYP450)Inhibition Assay is a fluorescence-based assay using a CYP isozyme forscreening of compounds of the invention to determine the level of CYP450inhibition by a specific compound. The assay is based on the CYPinhibition kit described by Vivid CYP450 Screening Kit Protocol, 2005,Invitrogen Corporation (Invitrogen Corporation, 1600 Faraday Avenue,Carlsbad, Calif. 92008, USA).

This assay is designed to assess compounds by quantifying the inhibitionof the predominant human CYP450 isozymes involved in hepatic drugmetabolism. It is based on the principle derived from the testing ofmany pharmacologically active compounds for their ability to serve assubstrates and inhibitors for the major Drug Metabolizing Enzymes,primarily CYPs, or for their interference with the metabolism ofexisting drugs. The standard method for evaluating specific CYP isozymeinhibition is to determine the conversion of a probe substrate (Table 4)into its metabolite, in the presence and absence of the potentialinhibitor. Quantification of the metabolite is achieved by HPLC or byusing a probe substrate that is metabolized into a fluorescent product(fluorescent assay).

Four CYP isozymes were investigated: CYP3A4, 2C9, 2C19 and 2D6. Inparticular, CYP3A4 is shown to be one of the most important isozymeinvolved in the metabolism of drugs in the body (seehttp://medicine.iupui.edu/flockhart/table.htm). A drug that inhibits aspecific CYP isozyme may decrease the metabolism of the drug andincrease serum concentrations of drugs that are substrates for thatisoenzyme. The CYP3A4 data reported below can be useful to predictpotential clinical drug-drug interactions for a particular compound.

TABLE 4 CYP450 ISOZYMES (CYP) AND SUBSTRATES USED Substrate CYP AcronymStructure Name 3A4 BOMCC 7-(benzyloxymethoxy)-3-cyanocoumarin 2C19 EOMCC7-(ethoxymethoxy)-3-cyanocoumarin 2C9 BOMF (benzyloxymethoxy)fluorescein2D6 MOBFC 7-(4-methoxybenzyloxy)-4-trifluoromethylcoumarin

TABLE 5 CYP450 ISOZYME INHIBITORS Con- centration % Iso- in 10 μMInhibition in zyme Inhibitor assay 10 μM assay IC₅₀ (nM) 3A4Ketoconazole 0.1 μM 50 +/− 10% 88 +/− 30 nM 2C9 Sulfaphenazole 0.420 μM50 +/− 15% 345 +/− 20 nM 2C19 Ketoconazole 7.62 μM 65 +/− 10% 3132 +/−680 nM 2D6 Quinidine 0.0137 μM 55 +/− 15% 15 +/− 5 nM

TABLE 6 TERMINOLOGY Name Definition Regeneration 100x consists of 333 mMGlucose-6-phosphate and System 40 U/mL Glucose-6-phosphate dehydrogenasein 100 mM (RS) Potassium Phosphate Buffer (pH 8.0). BaculosomesMicrosomes prepared from insect cells that were infected (Bac) withbaculovirus containing the cDNAs for human CYP isozyme (1 μM specificP450 content) and rabbit NADPH reductase. NADP⁺ Nicotinamide adeninedinucleotide phosphate at 10 μM in potassium phosphate buffer (100 mM,pH 8.0). Conversion of NADP+ into NADPH by the regeneration system isrequired to start the CYP450 reaction. Reaction Contains 100 or 200 mMpotassium phosphate buffer. Buffer Pre-Mix Contains reaction buffer, RS,Bac. Prepare separately for each isozyme. Substrate Contains reactionbuffer, substrate (BOMCC, EOMCC, Mix BOMF, or MOBFC), and NADP+. Prepareseparately for each isozyme.

This assay can be used for single concentration screening or for IC₅₀determination. In a single concentration screening assay, the finalassay concentration of the test compound is 10 μM. In an IC₅₀determination assay, IC₅₀ may be determined using a 3, 6, or 12 pointcurve in triplicate with a chosen starting concentration dilutedserially.

Preparation Stage:

In the Preparation Stage, the test compounds, controls (acetonitrile(ACN) or dimethyl sulfoxide (DMSO) and No Baculosomes), and knowninhibitors (Table 5) were diluted to 10% ACN or DMSO in water atappropriate concentrations. The Premix and Substrate Mix solutions werealso prepared per kit instructions. The Premix consisted of P450Baculosomes, regeneration system (RS), and Vivid® CYP450 reactionbuffer. The Substrate Mix consisted of Vivid® substrate, NADP+ andVivid® CYP450 reaction buffer.

Assay Stage:

In the Assay Stage, 30 μL water was added to each well of a 96-wellassay plate. Then 10 μL of the 10% ACN or DMSO in water stocks of thetest compounds, negative controls, or known inhibitors were added todesignated wells according to the assay plate layout. The third step wasto add 50 μL of the Premix solution to each working well (except for NoBaculosomes control wells, 50 μL buffer was added instead). The assayplate was then pre-warmed at ambient temperature in the dark for 20minutes. When pre-warming was completed, 10 μL of the Substrate Mixsolution was added to each working well (including the No Baculosomescontrol wells). This resulted in a final 1% ACN or DMSO concentration.The assay plate was immediately placed in a PolarStar plate reader toread initial fluorescence. The assay plate was again incubated atambient temperature in the dark for 20, 30, or 60 minutes depending onthe reaction time of the isozyme (Table 7). 10 μL of the stop reagentwas added to each working well and final fluorescence was read.

TABLE 7 ISOZYME REACTION TIME AND STOP REAGENT Reaction Isozyme Time(min) Concentration of Stop Reagent 3A4 20 10 μM Ketoconazole 2C19 20 30μM Ketoconazole 2C9 30 10 μM Sulfaphenazole 2D6 60  1 μM QuinidineData Analysis:

The difference between the initial and final fluorescence readings wasused to calculate percent inhibition. The ACN or DMSO readingsrepresented 0% inhibition and the No Baculosomes readings represented100% inhibition. Percent inhibition by the compound or known inhibitorwas calculated based on comparison with the solvent (ACN or DMSO)control and the No Baculosomes control. To minimize any fluorescencecompound or background effect, the relative fluorescence unit (RFU)initial was substrated from the RFU final.

Determine the % inhibition for each compound or control for each CYP450isozyme:

${\%\mspace{14mu}{Inhibition}} = {\frac{\begin{matrix}{{{Compound}\mspace{14mu}\left( {{RFU}\mspace{14mu}{final}\text{-}{intial}} \right)} -} \\{{DMSO}\mspace{14mu}{control}\mspace{14mu}\left( {{RFU}\mspace{14mu}{final}\text{-}{intial}} \right)}\end{matrix}}{\begin{matrix}{{{NoBac}\mspace{14mu}\left( {{RFU}\mspace{14mu}{final}\text{-}{intial}} \right)} -} \\{{DMSO}\mspace{14mu}{control}\mspace{14mu}\left( {{RFU}\mspace{14mu}{final}\text{-}{intial}} \right)}\end{matrix}} \times 100}$

Representative compounds of the invention, when tested in the aboveassay demonstrated percent inhibition of the CYP3A4 isozyme as set forthbelow in Table 8 wherein “A” refers to percent inhibition of less than50% at 10 μM and “B” refers to percent inhibition of greater than 50% at10 μM. The Example numbers provided in Table 8 correspond to theExamples herein:

TABLE 8 % Inhibition Ex. No. Compound Name of CYP3A4 12-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)- A one1.1 1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.21′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 1.31′-{[2,5-dimethyl-1-(1-methylethyl)-1H-pyrrol-3- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one1.4 5-(benzyloxy)-1′-[(5-chloro-2-thienyl)methyl]spiro[1-benzofuran- B3,3′-indol]-2′(1′H)-one 1.57′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)- B one1.6 1′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 1.71′-[(4-bromo-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 1.81′-(1-benzofuran-2-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 1.91′-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one1.10 (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- A2′(1′H)-one 1.10(3S)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- B2′(1′H)-one 1.11(R)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′- Aindolin]-2′-one 1.11(S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- A2′(1′H)-one 1.12 (8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-A dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one1.13 (8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 1.141′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-B 8,3′-indol]-2′(1′H)-one 1.151′-{[5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one1.16 1′-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one1.17 1′-(5-methoxypyridin-3-yl)spiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 2.31′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]- A2′(1′H)-one 2.6 1′-(4-methoxybenzyl)-3-methylspiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 2.91′-(diphenylmethyl)-5-fluorospiro[1-benzofuran-3,3′-indol]- A2′(1′H)-one 2.11 1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.141′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole- A7,3′-indol]-2′(1′H)-one 2.161′-(diphenylmethyl)-3-methylspiro[furo[2,3-f][1,3]benzoxazole- A7,3′-indole]-2,2′(1′H,3H)-dione 2.226-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H- Bspiro[benzofuran-3,3′-indolin]-2′-one 2.235-bromo-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-2H- Bspiro[benzofuran-3,3′-indolin]-2′-one 2.246′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine- B8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one 2.256-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H- Bspiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5- b]furan]-7(6H)-one2.26 6-(((R)-tetrahydrofuran-2-yl)methyl)-2,3,5′,6′-tetrahydro-2′H- Aspiro[[1,4]dioxino[2,3-f]indole-8,3′-benzofuro[6,5- b]furan]-7(6H)-one2.27 6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-B spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one 2.281-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro- B1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)- onehydrochloride 2.291-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-1H- Aspiro[furo[3,2-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one hydrochloride2.30 4-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H- Bspiro[furo[2,3-g][1,4]benzoxazine-8,3′-indol]-2′(1′H)-one 2.311′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2- Bg][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one 2.342,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one2.35 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one2.36 2,2-difluoro-1′-{[3-(trifluoromethyl)pyridin-2- Ayl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one2.38 3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one 2.396-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 2.406-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 2.411′-(4-methoxybenzyl)-3-methylspiro[furo[2,3- Bf][1,2]benzisoxazole-7,3′-indol]-2′(1′H)-one 2.451′-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.495′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 2.502′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile 2.53 phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indole]-4′-carboxylate 2.541′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihyrdospiro[1,4- Adioxino[2,3-g][1,3]benzodioxine-4,3′-indol]-2′(1′H)-one 2.611′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]- A2′(1′H)-one 2.634′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 2.644′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 2.656-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4- Adioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]- 7(6H)-one 2.666′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 36-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.14′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- B2′(1′H)-one 3.2 6-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.35,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.45′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- B2′(1′H)-one 3.56′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- B2′(1′H)-one 3.63-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)- A one3.7 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one A 3.85-fluoro-spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.102,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- A 2′(1′H)-one3.11 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]- A2′(1′H)-one 3.122-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one A 3.133-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]- A2,2′(1′H,3H)-dione 3.141-methylspiro[furo[3,2-f][1,3]benzoxazole-7,3′-indole]- A2,2′(1H,1′H)-dione 3.157′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- A2′(1′H)-one 3.167′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- A2′(1′H)-one 3.174′-fluoro-7′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-2′(1′H)-one 3.216,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)- A one 3.221-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]- A2,2′(1′H,3H)-dione 3.234-methyl-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′- Aindoline]-2′,3(2H)-dione 3.242,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)- A one3.25 (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)- Aone 3.26 (3R)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-B one 3.28 2′,3′,5,6-tetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,8′- B[1,4]dioxino[2,3-f]indol]-7′(6′H)-one 3.296-methoxy-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]- A5-carbonitrile 3.306-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5- Acarbonitrile 3.324′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 3.334′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 3.344′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-2′(1′H)-one 3.354′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 3.40spiro[indole-3,3′-thieno[2,3-f][1]benzofuran]-2(1H)-one 5,5′- A dioxide3.41 spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one A3.42 6-chloro-2,3-dihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′- Aindol]-2′(1′H)-one 3.445,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one B 3.455′,6′,7′,8′-tetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]- B2(1H)-one 3.466-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one A 3.475-(2-methoxyethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one A 3.482,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)- A one3.49 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′- B[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one 3.504′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-2′(1′H)-one 3.51spiro[furo[2,3-g]quinoxaline-8,3′-indol]-2′(1′H)-one A 41′-(tetrahydro-2H-pyran-2-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.21′-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.31′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.41′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-2′(1′H)-one 4.5 1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.61′-(tetrahydro-2H-pyran-4-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.7methyl 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate 4.81′-(1,4-dioxan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.91′-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.101′-(tetrahydro-2H-pyran-3-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.11methyl 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- A3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate 4.121′-(2-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- A3,3′-indol]-2′(1′H)-one 4.131′-(4-fluorobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-2′(1′H)-one 4.141′-benzyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-2′(1′H)-one 4.151′-(biphenyl-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.161′-(tetrahydrofuran-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.171′-[(3-bromoisoxazol-5-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.181′-[(5-bromofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.201′-(oxetan-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.211′-[(1-ethyl-1H-imidazol-5-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.223-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]benzonitrile 4.234-((2′-oxo-5,6-dihydro-2H-spiro[benzofuro[6,5-b]furan-3,3′- Aindoline]-1′-yl)methyl)benzonitrile 4.244′-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]biphenyl-2-carbonitrile 4.251′-{(2S)-2-[(benzyloxy)methoxy]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.261′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.271′-(2,1,3-benzoxadiazol-5-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.281′-(2,1,3-benzothiadiazol-5-ylmethyl)-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.291′-[(4-benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 4.334′-chloro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.344′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.354′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 4.361′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.371′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.381′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.401′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-onehydrochloride 4.41 1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.421′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride 4.431′-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.441′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.451′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.461′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.471′-(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.481′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.49(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.50(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.51(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.521′-(pyridin-2-ylmethyl)-6,7-dihydrospiro[benzo[1,2-b:4,5- Ab′]difuran-3,3′-indol]-2′(1′H)-one 4.531′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H- Aspiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one 4.541′-{[5-(trifluoromethyl)furan-2-yl]methyl}-3,4-dihydro-2H- Bspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)- one 4.551′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3- Ah][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 4.562-methyl-1′-(3-methylbutyl)spiro[furo[2,3-f][1,3]benzothiazole- B7,3′-indol]-2′(1′H)-one 4.572-methyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3- Bf][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one 4.582-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3- Af][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one 4.591-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2- Ag][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione 4.601-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Af][1,3]benzoxazole-7,3′-indole]-2,2′(1H,1′H)-dione 4.616-methoxy-5-methyl-1′-[(2R)-tetrahydrofuran-2- Aylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.626-methoxy-5-methyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran- B3,3′-indol]-2′(1′H)-one 4.636-methoxy-5-methyl-1′-(tetrahydro-2H-pyran-2- Bylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.645-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 4.655-fluoro-6-methoxy-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran- A3,3′-indol]-2′(1′H)-one 4.665-fluoro-6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 4.671′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]- A2′(1′H)-one 4.68 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-A benzofuran-3,3′-indol]-2′(1′H)-one 4.701′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3,6,7- Btetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)- one 4.721′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.73(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Byl)acetonitrile 4.74 7′-(trifluoromethyl)-1′-{[5-(trifluoromethyl)-2- Bfuryl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one4.75 1′-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-B f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.761′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′- B(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.771′-[(2-isopropyl-1,3-oxazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.78 tert-butyl[1-cyclopropyl-3-(2′-oxospiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-1′(2′H)- yl)propyl]carbamate 4.791′-[4-(methylsulfanyl)benzyl]spiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 4.803-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Byl)propanenitrile 4.811′-[(2-bromo-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.821′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one4.83 6-Fluoro-5-methoxy-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 4.844′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- A1′(2′H)-yl)acetonitrile 4.851′-[(2-amino-1,3-thiazol-4-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.864′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.871′-[(5-chloro-2-thienyl)methyl]-2′-oxo-1′,2′-dihydrospiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile 4.881′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]-2′-oxo-1′,2′- Bdihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′- carbonitrile4.89 4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.904′-chloro-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.914′-chloro-1′-[(2-isopropyl-1,3-thiazol-4-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 4.924′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3- Bthiazol-4-yl]methyl}spiro[furo[2,3-f][1,3] benzodioxole-7,3′-indol]-2′(1′H)-one 4.933′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 4.943-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]benzonitrile 4.951′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.964-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]benzonitrile 4.971′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.981′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.991′-(4-isoxazol-5-ylbenzyl)-3-methylspiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 4.1001′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1011′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1021′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1034′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1041′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1052′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1-benzofuran- A3,3′-indole]-6-carbonitrile 4.1063-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile 4.107(8S)-1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.108(8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.109(S)-1′-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6- Ab][1,4]dioxine-8,3′-indolin]-2′-one 4.1101′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1111′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2′-oxo-1′,2′- Adihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile 4.1121′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1131′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.114(8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.116(8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1181′-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1191′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1201′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1211′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 4.1221′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 4.1241′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole- A8,3′-indol]-2′(1′H)-one 4.1251′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole- A8,3′-indol]-2′(1′H)-one 4.1266-chloro-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[3,2- Bf][1,4]benzodioxine-9,3′-indol]-2′(1′H)-one 4.1291-[(2R)-tetrahydrofuran-2-ylmethyl]-5′,6′,7′,8′- Atetrahydrospiro[indole-3,3′-naphtho[2,3-b]furan]-2(1H)- one 4.1301′-(pyridin-2-ylmethyl)spiro[furo[2,3-g]quinoxaline-8,3′-indol]- A2′(1′H)-one 5 1′-[(2-methoxypyrimidin-5-yl)methyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.17′-chloro-1′-((5-(trifluoromethyl)furan-2-yl)methyl)-5,6-dihydro- B2H-spiro[benzofuro[6,5-b]furan-3,3′-indolin]-2′-one 5.2(3R)-1′-(3-methylbutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 5.3(3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-2′(1′H)-one 5.4(3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 5.5(3R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.6(3S)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 5.7(3S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 5.83-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3- Bf][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione 5.91′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.101′-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.111′-{[3-(trifluoromethyl)pyrazin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.121′-{[4-(trifluoromethyl)pyridin-3-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.131′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.141′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.151′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.16(8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.17(8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.18(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.196-methyl-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[1,4- Adioxino[2,3-f]indole-8,3′-indole]-2′,7(1′H,6H)-dione 5.204′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.211′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.221′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 5.231′-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.259-fluoro-1′-(pyridin-2-ylmethyl)-2,3-dihydro-spiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.269-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.279-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.281′-(pyridin-2-ylmethyl)-7,8-dihydro-6H-spiro-[furo[2,3- Bg]chromene-3,3′-indol]-2′(1′H)-one 5.291′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-7,8-dihydro-6H- Aspiro[furo[2,3-g]chromene-3,3′-indol]-2′(1′H)-one 5.311-(pyridin-2-ylmethyl)spiro[indole-3,3′-thieno[2,3- Af][1]benzofuran]-2(1H)-one 5,5′-dioxide 5.321′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 5.331′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 5.346-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran- A3,3′-indol]-2′(1′H)-one 5.355-(2-methoxyethoxy)-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran- A3,3′-indol]-2′(1′H)-one 5.361′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine- A7,3′-indol]-2′(1′H)-one 5.371′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihyrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]- 2′(1′H)-one 5.386-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Ayl)methyl]pyrimidine-2,4(1H,3H)-dione 61′-[(5-Chloro-1,2,4-thiadiazol-3-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.14′-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3- Byl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one6.2 5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 6.31′-[(3-chlorothiophen-2-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.41′-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one6.5 1′-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4- Byl}methyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one6.6 1′-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 6.71′-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one6.8 1′-([1,3]oxazolo[4,5-b]pyridin-2-ylmethyl)spiro[furo[2,3- Af][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 7.11′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.2 methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate 7.4(R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-2′(1′H)-one 7.51′-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-2′(1′H)-one 7.61′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.71′-(2-ethoxyethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.81′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.91′-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3- Ag][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.101′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine- A8,3′-indol]-2′(1′H)-one 7.111′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one 7.121′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.131′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.141′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.15(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.16N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′-(2′H)- yl)methyl]benzenesulfonamide7.17 1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.181′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.191′-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.201′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.211′-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.221′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.231′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 7.241′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.251′-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.261′-[(2-fluoro-5-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.271′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 7.281′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 81′-[(2S)-1,4-dioxan-2-ylmethyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 8.17′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.27′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.34′-fluoro-7′-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.41′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-2′(1′H)-one 8.5(8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 8.6(8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 8.8(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 8.91′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7- Adihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]- 2′(1′H)-one 8.101′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2- Ab:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one 8.111′-[(2R)-tetrahydrofuran-2-ylmethyl]-3,4-dihydro-2H- Aspiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)- one 8.121′-[(2R)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3- Ah][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 8.131′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3- Ah][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one 8.143-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H- Aspiro[benzofuro[6,5-d]oxazole-7,3′-indoline]- 2,2′(3H,6H)-dione 8.157′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H- Aspiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one 8.167′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro- A2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′- one 8.173′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 8.181′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 8.19(8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 93-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.11′-[2-(2-methoxyethoxy)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.21′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.31′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.41′-(4-pyridin-2-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.51′-(pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.61′-(pyrimidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.71′-(pyrazin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.81′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.91′-(pyridazin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.101′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.111′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.121′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.131′-(2H-benzotriazol-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 9.14 methyl2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- A3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.15 methyl3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.16 methyl4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- A3,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.171′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 9.185′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.196′-fluoro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 9.201′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.212-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[2,3- Af][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one 9.221′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2- Bmethylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]- 2′(1′H)-one 9.234-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7- Adihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]- 2′,3(2H)-dione9.24 3-methyl-1′-(pyridin-2-ylmethyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.253-methyl-1′-(pyridin-3-ylmethyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.263-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.275,6-dimethyl-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 9.285,6-dimethyl-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′- Aindol]-2′(1′H)-one 9.295-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 9.305-fluoro-6-methoxy-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 9.315,6-difluoro-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′- Bindol]-2′(1′H)-one 9.325,6-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 9.336-methoxy-1′-(pyridin-2-ylmethyl)-2H-spiro[benzofuran-3,3′- Aindolin]-2′-one 9.346-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]- B2′(1′H)-one 9.35 6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 9.366-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 9.371′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.381′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 9.39(8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.40 tert-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate 9.413-methyl-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.423-methyl-1′-{[3-(trifluoromethyl)pyridin-2- Byl]methyl}spiro[furo[3,2-f][1,2]benzisoxazoie-5,3′-indol]- 2′(1′H)-one9.43 1′-[3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.44 ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)acetate 9.451′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.466-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 9.476-methoxy-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 9.486-fluoro-2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2′-dihydrospiro[1- Bbenzofuran-3,3′-indole]-5-carbonitrile 9.506-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′- Bdihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 9.516-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′- Adihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 9.53 methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.541′-[2-(2-methoxyethoxy)ethyl]-3-methylspiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.553-methyl-1′-(3-methylbutyl)spiro[furo[3,2-f][1,2]benzisoxazole- B5,3′-indol]-2′(1′H)-one 9.563-methyl-1′-(pyrazin-2-ylmethyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.571′-[(3-fluoropyridin-2-yl)methyl]-3-methylspiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 9.58 methyl2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole- A5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate 9.59 methyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-1′(2′H)-yl)methyl]benzoate 9.601′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.645,6-difluoro-1′-(pyridin-2-ylmethyl)spiro[1-benzofuran-3,3′- Aindol]-2′(1′H)-one 9.655,6-difluoro-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 9.662-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione 9.671′-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2- Ae][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one 9.70(8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 9.716′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 9.726′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]- 7′(6′H)-one 9.734′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.744′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 9.756-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 9.765-(2-methoxyethoxy)-1′-[2-(2-methoxyethoxy)ethyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 101-(pyridazin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 111′-[(2-chloro-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.11′-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.21′-[(2-morpholin-4-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.31′-[(2-piperidin-1-yl-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.41′-[(2-methoxy-1,3-thiazol-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.51′-(piperidin-4-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 11.61′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.81′-[(1-ethylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.101′-[(1-methylpiperidin-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.123-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]benzoic acid 11.131′-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.141′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.151′-[(5-pyridin-4-ylfuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.161′-(4-pyridin-3-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.171′-[(2′-fluorobiphenyl-4-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.181′-{2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Byl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.19 4′-chloro-1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.20 4′-chloro-1′-[(5-cyclopropyl-1,2,4-oxadiazol-3- Byl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.21 4′-chloro-1′-{1-[5-(difluoromethyl)-1,2,4-oxadiazol-3- Byl]ethyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.22 1′-{[5-(difluoromethyl)-1,2,4-oxadiazol-3- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.23 1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.241′-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.254′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.26 1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-B f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.271′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.281′-{3-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.291′-[4-(5-methyl-4H-1,2,4-triazol-3-yl)benzyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.302-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]benzoic acid 11.314-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]benzoic acid 11.33N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxamide11.34 1′-(3-hydroxypropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 11.352′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′,5,6- Atetrahydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indole]- 4′-carbonitrile11.37 4′-[(dimethylamino)methyl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- A5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one11.38 4′-(pyrrolidin-1-ylmethyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- A5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one11.39 4′-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.411′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 11.421′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.431′-methyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-2′(1′H)-one 11.441′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.451′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.461′-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 11.476-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 11.48N-{2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′- Adihydrospiro[1-benzofuran-3,3′-indol]-6- yl}methanesulfonamide 11.496-hydroxy-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]- B2′(1′H)-one 11.506-hydroxy-1′-(3-methylbutyl)-5-(trifluoroacetyl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 11.526-[(3R)-pyrrolidin-3-ylamino]-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one 11.536-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 11.546-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 11.566-[(3S)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2- Aylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 11.586-[(3R)-pyrrolidin-3-yloxy]-1′-[(2R)-tetrahydrofuran-2- Aylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 11.601′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indole]-2′,5(1′H,6H)-dione 11.611′-(pyrrolidin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 11.62N-(1-methylethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1- carboxamide11.63 1′-[(4-methylpiperazin-1-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one hydrogen chloride 11.64(3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1- Ayl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride11.65 (3R)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1- Byl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride11.62 (3S)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.67(3R)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.68(3R)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.69(3S)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2″(1′H)-one 11.701′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 11.711′-[(3-methyl-2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 11.721′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3- Byl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- 2′(1′H)-one11.73 N-isopropyl-3-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-1′(2′H)-yl)ethyl]piperidine-1-carboxamide 11.745-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Byl)methyl]thiophene-3-carbonitrile 11.752′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindole]-7′-carbonitrile 11.771′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid 11.783′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one 11.793′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]- 2′(3′H)-one 11.802-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine- A8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile 11.81(8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.831′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.841′-[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.856-(5-methyl-1,2,4-oxadiazol-3-yl)-1′-(pyridin-2-ylmethyl)spiro[1- Abenzofuran-3,3′-indol]-2′(1′H)-one 11.863-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]benzoic acid 11.874-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]benzoic acid 11.901′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.921′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 11.94N-{3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)-yl)methyl]phenyl}methanesulfonamide 11.951′-[(1-oxydopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.971′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrobromide 11.98N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- B8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3- yl}methanesulfonamide 11.991′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride 11.1001′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-onehydrochloride 11.1011′-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrochloride 11.1021′-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.1031′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.104 1′-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 11.106(8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.107 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}spiro[furo[3,2- Be][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one 11.1086-chloro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]- 2′(1′H)-one11.109 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[3,2-f][1,4]benzodioxine-9,3′-indol]- 2′(1′H)-one11.110 1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one11.111 5,6-difluoro-1′-(piperidin-4-ylmethyl)spiro[1-benzofuran-3,3′- Bidol]-2′(1′H)-one hydrochloride 11.1125,6-difluoro-1′-[(1-methylpiperidin-4-yl)methyl]spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 12N-(cyclohexylmethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.1N-(2-methoxyethyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.2N-hexyl-N-methyl-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.3N-(2-ethylbutyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.4N-(2,4-dimethylphenyl)-3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.53-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(2-phenylpropyl)benzamide 12.6N-[(1S)-1-cyclohexylethyl]-3-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.7N-[(1R)-1-cyclohexylethyl]-3-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.8N-(4-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.9N-(2-ethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.10N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.11N-(2-methoxyphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.12N-(2-fluorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.13N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.14N-(3-fluoro-2-methylphenyl)-2-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.15N-heptyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.16N-(2-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.171′-[2-(piperidin-1-ylcarbonyl)benzyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 12.18N-butyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.19N-(3-methylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.20N-(2-fluoro-5-methylphenyl)-2-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.21N-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.22N-[2-(4-methoxyphenyl)ethyl]-2-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.23N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.24N-[2-(4-chlorophenyl)ethyl]-2-[(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.25N-(2-methoxyphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.264-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-[2- (trifluoromethyl)phenyl]benzamide 12.274-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]-N-phenylbenzamide 12.28N-methyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.29N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.304-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(2-thiophen-2- ylethyl)benzamide 12.314-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]benzamide 12.32N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.331′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 12.34N-(2-ethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.35N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.36N-(3-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.37N-(2,4-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.384-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)methyl]-N-(thiophen-2- ylmethyl)benzamide 12.39N-ethyl-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.40N-(2-methoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.41N-(2-ethoxyethyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.42N-cyclobutyl-4-[(2-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3-indol]-1(2H)-yl)methyl]benzamide 12.434-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]-N-1,3-thiazol-2-ylbenzamide 12.44N-(3-fluoro-2-methylphenyl)-4-[(2′-oxo-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.45N-(2-ethylbutyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide 12.462-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)acetamide 12.47N-(4-ethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.48N,N-diethyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.49N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.50N-[3-(1-methylethoxy)propyl]-2-(2′-oxo-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.512-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)-N-propylacetamide 12.52N-methyl-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- B3,3′-indol]-1′(2′H)-yl)-N-phenylacetamide 12.53N-(2,5-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Ab:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.54N-(2,4-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.55N-(2,3-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.56N-(2,6-dimethylphenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide 12.57N-methyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3- carboxamide 12.585-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)- Byl)methyl]-2-(trifluoromethyl)furan-3-carboxamide 12.59N,N-dimethyl-5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3- carboxamide 12.604-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]benzamide 12.613-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]benzamide 12.62N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzamide 12.63N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide 12.64N-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide dihydrochloride 12.65N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)- yl)methyl]benzamide 135-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid 13.1N,N-dimethyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxamide 13.2N-methyl-5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2- carboxamide 13.32-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Aindol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide 13.4N,N-dimethyl-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4- carboxamide13.5 N-cyclopropyl-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide 13.6N-(1-methylethyl)-2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide 13.7N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide 13.11N-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)propyl]-2-(trifluoromethoxy)benzamide 141′-[(2S)-2-hydroxypropyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Ab′]difuran-3,3′-indol]-2′(1′H)-one 14.11′-[(2S)-2-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 14.21′-{(2S)-2-[(4-fluorobenzyl)oxy]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 14.31′-[(2S)-2-(pyridin-2-ylmethoxy)propyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 14.41′-(3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran- A3,3′-indol]-2′(1′H)-one 14.51′-(4,4,4-trifluoro-3-hydroxybutyl)-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 15.11′-{3-[(3-methylbutyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one hydrochloride 15.21′-{3-[butyl(methyl)amino]propyl}-5,6-dihydrospiro[benzo[1,2- Bb:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one hydrochloride 15.31′-{3-[(2,2,2-trifluoroethyl)amino]propyl}-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-onehydrochloride 15.43-{[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′- Bindol]-1′(2′H)-yl)propyl]amino}propanenitrile hydrochloride 164′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.14′-[(E)-2-(4-fluorophenyl)ethenyl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.24′-dibenzo[b,d]thiophen-4-yl-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.34′-(1-benzothiophen-3-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- B5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one16.4 4′-(1-methyl-1H-indol-5-yl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]- B5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one16.5 4′-[3,5-bis(trifluoromethyl)phenyl]-1′-[(2R)-tetrahydrofuran-2- Bylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.64′-(4-phenoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.74′-[4-(2-methylpropoxy)phenyl]-1′-[(2R)-tetrahydrofuran-2- Aylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.84′-(4-butoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Adihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.94′-(4-methoxyphenyl)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.104′-pyrimidin-5-yl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6- Bdihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]- 2′(1′H)-one 16.114′-[6-(dimethylamino)pyridin-3-yl]-1′-{[5-(trifluoromethyl)furan-2- Byl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one 16.121′-[(5-chloro-2-thienyl)methyl]-4′-[6-(dimethylamino)pyridin-3- Byl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)- one 16.131′-[(5-chloro-2-thienyl)methyl]-4′-(3-furyl)spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.144′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.151′-methyl-4′-(2-oxo-2H-chromen-7-yl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.161′-methyl-4′-(2-oxopyrrolidin-1-yl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.171′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.181′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.194′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.20N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′- yl)cyclobutanecarboxamide 16.21N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′-yl)-2- (trifluoromethyl)benzamide16.22 N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′- yl)methanesulfonamide 16.23N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′- yl)cyclohexanecarboxamide 16.24N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′- yl)cyclopentanecarboxamide 16.25N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide 16.26N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′- yl)cyclopropanecarboxamide 16.27N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-4′-yl)benzamide 16.282-methoxy-N-(1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide 16.29N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide 16.30N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′-yl)pentanamide 16.312,2-dimethyl-N-(1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide 16.32N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-4′-yl)hexanamide 16.33N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-4′-yl)heptanamide 16.342-(2-methoxyethoxy)-N-(1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide 16.351-hexyl-3-(1′-methyl-2′-oxo-1′2,2′,3-tetrahydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-4′-yl)urea 16.361-cyclopentyl-3-(1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 4′-yl)urea16.37 1-cyclohexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 4′-yl)urea16.38 N-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-A g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.39N-cyclopentyl-1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.411′-methyl-4′-(pyrrolidin-1-ylcarbonyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.421′-methyl-2′-oxo-N-pentyl-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.43N-(2-methoxyethyl)-1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.44N-(4-fluorobenzyl)-1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.45N-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.461′-methyl-2′-oxo-N-(pyridin-2-ylmethyl)-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.47N-(4-fluorophenyl)-1′-methyl-2′-oxo-1′,2,2′,3- Atetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.504′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.514′-hydroxy-2,3-dihydrospiro[furo[2,3-g] [1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 16.52 4′-hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-A g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.531′-methyl-4′-(pyridin-2-yloxy)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.544′-[2-(2-methoxyethoxy)ethoxy]-1′-methyl-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.551′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.561′-methyl-4′-[4-(trifluoromethyl)phenoxy]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.574′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.581′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.594′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7- Bdihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′- indolin]-2′-one16.60 4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H- Bspiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one 16.61(7S)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 16.62(7R)-4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole- B7,3′-indol]-2′(1′H)-one 16.63(7R)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-2′(1′H)-one 16.64(7S)-4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindol]-2′(1′H)-one 16.65(7S)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- B2′(1′H)-one 16.66(7R)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]- B2′(1′H)-one 16.671′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.684′-furan-3-yl-1′-methyl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.691′-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.701′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.711′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile 16.731′-methyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3- Bf][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one 16.741′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.754′-(3,5-dimethylisoxazol-4-yl)-1′-methyl-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.77N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.78N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-4′-carboxamide 16.794′-(3-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.801′-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.811′-methyl-4′-(3-morpholin-4-ylphenoxy)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.824′-[(6-methoxypyridin-3-yl)oxy]-1′-methyl-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.834′-(1,3-benzodioxol-5-yloxy)-1′-methyl-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 16.844′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.851′-methyl-4-(pyridine-2-ylmethoxy)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.861′-methyl-4-(4-fluorobenzyloxy)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.874′-(4-fluorophenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 16.881′-[(5-chloro-2-thienyl)methyl]-5-(6-methoxypyridin-3-yl)spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one 171′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4- Bb′]difuran-3,3′-indol]-2′(1′H)-one 17.11′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 17.21′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 18 ethyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindole]-1′(2′H)-carboxylate 18.1 tert-butyl4′-bromo-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′- Bindole]-1′(2′H)-carboxylate 18.2 tert-butyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indole]-1′(2′H)-carboxylate 191′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH- Abis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 206-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D- galactopyranose 211′-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- A8,3′-indol]-2′(1′H)-one 221′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-2′(1′H)-one 23 1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-A dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 244′-acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 251′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 264′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 274′-(5-hydroxy-1H-pyrazol-3-yl)-1′-methyl-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 281′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 29.11′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-3-methylspiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one hydrochloride 29.21′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-onehydrochloride 30 1′-[4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 312′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indole]-5′-carboxamide 321′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 32.11′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 32.21′-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 33.25,6-difluoro-1′-{4-[(3R)-pyrrolidin-3-ylamino]benzyl}spiro[1- Bbenzofuran-3,3′-indol]-2′(1′H)-one hydrochloride 33.31′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g] [1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 33.41′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 341′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3- Bg][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 351′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 35.11′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 361′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3- Adihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 371′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one 38N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3- Ag][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide 391′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3- Bdihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]- 2′(1′H)-one 416-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Aindol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrile 426-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- Bindol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide 443-amino-1′-(4-methoxybenzyl)spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.13-amino-1′-(pyridin-2-ylmethyl)spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.23-amino-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[3,2- Af][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 44.33-amino-1′-[2-(trifluoromethyl)benzyl]spiro[furo[3,2- Bf][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one 456-hydroxy-2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′- Adihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 45.16-hydroxy-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′- Adihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile 461′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′- Bindol]-2′(1′H)-one 46.11′-(pyridin-2-ylmethyl)-1H-spiro[furo[3,2-f]indazole-5,3′-indol]- A2′(1′H)-one 46.2 1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6- Bdihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A compound of formula (I):

wherein: n is 1 or 2; one of J and K is —CH₂— and the other is —O—; orboth J and K are each —CH₂—; R¹ is (6-methylpyridin-2-yl)methyl,pyridin-3-ylmethyl, diphenylmethyl, pentyl, isopentyl,(5-(trifluoromethyl)furan-2-yl)methyl, tetrahydrofuran-2-ylmethyl,3-methylbutyl, tetrahydro-2H-pyran-4-ylmethyl,tetrahydro-2H-pyran-2-ylmethyl,(5-chloro-1-methyl-1H-imidazol-2-yl)methyl, pyridin-2-ylmethyl,(2R)-1,4-dioxan-2-ylmethyl, 1,4-dioxan-2-ylmethyl, 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl, 2,3-dihydro-1,4-benzodioxin-6-ylmethyl,[5-(trifluoromethyl)furan-2-yl]methyl, 3-(trifluoromethyl)benzyl,(5-methoxycarbonylfuran-2-yl)methyl, 2(2-methoxyethoxy)ethyl,5-carboxyfuran-2-ylmethyl, 5-(dimethylaminocarbonyl)furan-2ylmethyl,3-(trifluoromethyl)pyridin-2-yl]methyl or (5-hydroxypyridin-2-yl)methyl;each R² is hydrogen; or two adjacent R²'s, together with the adjacentcarbons to which they are attached, form a fused thiazolyl ring or afused dioxinyl ring; as a stereoisomer, enantiomer, tautomer thereof ormixtures thereof; or a pharmaceutically acceptable salt or prodrugthereof.
 2. The compound of claim 1 wherein J is —O— and K is —CH₂—. 3.The compound of claim 2 selected from:(8R)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-methylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one;6-((5-(trifluoromethyl)furan-2-yl)methyl)-2,3,3′,7′-tetrahydro-2′H-spiro[[1,4]dioxino[2,3-f]indole-8,8′-benzofuro[5,6-b][1,4]dioxin]-7(6H)-one;2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1-[(5-chloro-1-methyl-1H-imidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-[(2S)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(1,4-dioxan-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3,5-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(S)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[3-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;methyl5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate;1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8R)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(2S)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]-benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylicacid; orN,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide.4. The compound of claim 1 wherein J is —CH₂— and K is —O—.
 5. Thecompound of claim 4 which is1′-[(2R)-tetrahydrofuran-2-ylmethyl]-4H-spiro[furo[3,2-g][1,3]benzodioxine-6,3′-indol]-2′(1′H)-one.6. The compound of claim 1 where both J and K are each —CH₂—.
 7. Thecompound of claim 6 selected from:1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one;or1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one.8. A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of claim 1, as a stereoisomer, enantiomer,tautomer thereof or mixtures thereof; or a pharmaceutically acceptablesalt or prodrug thereof.
 9. A method of treating pain in a mammal,wherein the method comprises administering to the mammal in need thereofa therapeutically effective amount of a compound of claim 1, as astereoisomer, enantiomer, tautomer thereof or mixtures thereof; or apharmaceutically acceptable salt or prodrug thereof.
 10. The method ofclaim 9, wherein the pain is selected from the group consisting ofneuropathic pain, inflammatory pain, visceral pain, cancer pain, dentalpain, chemotherapy pain, trauma pain, surgical pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,and peripheral nerve injury, and combinations thereof.
 11. The method ofclaim 9, wherein the pain is associated with a disease or conditionselected from HIV, HIV treatment induced neuropathy, heat sensitivity,sarcoidosis, irritable bowel syndrome, Crohns disease, multiplesclerosis, amyotrophic lateral sclerosis, pruritis,hypercholesterolemia, benign prostatic hyperplasia, diabetic neuropathy,peripheral neuropathy, rheumatoid arthritis, osteoarthritis, paroxysmaldystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,Paroxysmal Episodic Pain Disorder, cancer, epilepsy, partial and generaltonic seizures, restless leg syndrome, arrhythmias, ischaemic conditionscaused by stroke or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation.
 12. A method of treating painin a mammal by the inhibition of ion flux through a voltage-dependentsodium channel in the mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of acompound of claim 1, as a stereoisomer, enantiomer, tautomer thereof ormixtures thereof; or a pharmaceutically acceptable salt or prodrugthereof.
 13. A method of decreasing ion flux through a voltage-dependentsodium channel in a cell in a mammal, wherein the method comprisescontacting the cell with a compound of claim 1, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof; or a pharmaceuticallyacceptable salt or prodrug thereof.
 14. A method of treatinghypercholesterolemia in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim 1, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt orprodrug thereof.
 15. A method of treating benign prostatic hyperplasiain a mammal, wherein the method comprises administering to the mammal inneed thereof a therapeutically effective amount of a compound of claim1, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof;or a pharmaceutically acceptable salt or prodrug thereof.
 16. A methodof treating pruritis in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of claim 1, as a stereoisomer, enantiomer, tautomerthereof or mixtures thereof; or a pharmaceutically acceptable salt orprodrug thereof.
 17. The method of claim 9 wherein the pain is selectedfrom trigeminal neuralgia, post-herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia.
 18. A compound of formula (I):

wherein: n is 1 or 2; one of J and K is —CH₂— and the other is —O—; orboth J and K are each —CH₂—; R¹ is methyl, cyclopropyl, carboxymethyl,(3-carboxy)benzyl, (3-methylsulfonylamino)benzyl,[(3-methylsulfonylamino)pyridin-2-yl]methyl,[(3-carboxy)pyridin-2-yl]methyl, [(ethoxy)carbonyl]methyl,2-cyclopropylethyl, 1,3-thiazol-5-ylmethyl, 3-methoxypropyl,(6-methylpyridin-2-yl)methyl, pyridin-3-ylmethyl,[3-(cyano)pyridine-2-yl]methyl, [3-(difluoromethyl)pyridin-2-yl]methyl,3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl,[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl,[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl,[4-(trifluoromethyl)pyridin-2-yl]methyl,(4-methyl-1,2,5-oxadiazol-3-yl)methyl, pyrazin-2-ylmethyl,pyrimidin-2-ylmethyl, (1-methyl-1H-benzotriazol-5-yl)methyl,[2-(tert-butoxycarbonylamino)pyridin-5-yl]methyl,[6-(dimethylamino)pyridin-3-yl]methyl,[6-(dimethylamino)pyridin-2-yl]methyl,{6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl,(5-morpholin-4-ylpyridin-2-yl)methyl,[5-(dimethylamino)pyridin-2-yl]methyl, (6-aminopyridin-2-yl)methyl,(6-oxo-1,6-dihydropyridin-3-yl)methyl, (2-hydroxypyrimidin-5-yl)methyl,(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl,(6-aminopyridin-3-yl)methyl, [1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl,(5-hydroxypyridin-2-yl)methyl, (5-bromopyridin-2-yl)methyl,hydrazinocarbonylmethyl, [6-deoxy-D-galactopyranose]-6-yl,(6-morpholin-4-ylpyridin-3-yl)methyl,[3-(methylsulfonyl)pyridin-2-yl]methyl,(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl, (3-bromopyridin-2-yl)methyl,[(2-imidoformamido)pyridine-5-yl]methyl, (6-cyanopyridin-2-yl)methyl,(6-aminocarbonylpyridin-2-yl)methyl, diphenylmethyl, 4-methoxybenzyl,2-(fluoromethyl)benzyl, 2-ethoxyethyl, 4-fluorophenyl,(2-fluorophenylaminocarbonyl)methyl, 2-(2-methoxyethoxy)ethyl,4-isoxazol-5-ylbenzyl, 3-(benzyloxy)propyl, (2S)-2,3-dihydroxypropyl,4-methoxybutyl, pentyl, isopentyl, hexyl, 3-nitrobenzyl,[3-(trifluoromethyl)pyridin-2-yl]methyl,[5-(trifluoromethyl)pyridin-2-yl]methyl,[(tert-butoxycarbonylamino)pyridin-2-yl]methyl,(3-(trifluoromethyl)pyridin-2-yl)methyl,(5-(trifluoromethyl)furan-2-yl)methyl, tetrahydrofuran-2-ylmethyl,3-methylbutyl, cyanomethyl, 4-hydroxybenzyl, 3-cyanobenzyl,4-fluoro-3-methoxybenzyl, 4-cyanobenzyl,[6-(trifluoromethyl)pyridin-3-yl]methyl,[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl,(3-fluoropyridin-2-yl)methyl, (4-fluoropyridin-2-yl)methyl,(5-fluoropyridin-3-yl)methyl, (5-fluoropyridin-2-yl)methyl,(3-chloropyridin-2-yl)methyl, (3,5-difluoropyridin-2-yl)methyl,(3-pyridin-3-ylisoxazol-5-yl)methyl, (2,2-difluorocyclopropyl)methyl,2-oxobutyl, 2,1,3-benzothiadiazol-5-ylmethyl,2,1,3-benzoxadiazol-5-ylmethyl, 1,3-benzothiazol-2-ylmethyl,(1-methyl-1H-benzimidazol-2-yl)methyl,[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl, tert-butoxycarbonyl,[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl,(2-methoxypyrimidin-5-yl)methyl, (6-methoxypyridin-3-yl)methyl,(1-oxydopyridin-2-yl)methyl, (3-aminopyridin-2-yl)methyl,piperidin-4-ylmethyl, [1-(1-methylethyl)piperidin-4-yl]methyl,(1-methylpiperidin-4-yl)methyl, morpholin-2-ylmethyl,[4-(1-methylethyl)morpholin-2-yl]methyl, (4-methylmorpholin-2-yl)methyl,(2S)-morpholin-2-ylmethyl, [(2S)-4-methylmorpholin-2-yl]methyl,[5-(difluoromethyl)furan-2-yl]methyl, tetrahydro-2H-pyran-4-ylmethyl,tetrahydro-2H-pyran-2-ylmethyl,(5-chloro-1-methyl-1H-imidazol-2-yl)methyl,(6-chloropyridin-2-yl)methyl, (4,6-dimethoxypyrimidin-2-yl)methyl,[(3-methylaminocarbonyl)pyridin-2-yl]methyl,1-[2-(aminoethyl)aminocarbonylpyridin-3-yl]methyl, pyridin-2-ylmethyl,(2R)-1,4-dioxan-2-ylmethyl, 1,4-dioxan-2-ylmethyl, 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl, 3-hydroxypropyl, 3-phthalimidopropyl,3-aminobenzyl, (3-aminocarbonyl)benzyl, (4-aminocarbonyl)benzyl,(3-N,N-dimethylaminocarbonyl)benzyl, 4-(benzyloxy)benzy, 4-fluorobenzyl,2,3-difluorobenzyl, 3,5-difluorobenzyl, 2-chloro-4-fluorobenzyl,[3-(2-fluorophenyl)aminocarbonyl]benzyl, 3-(methoxycarbonyl)benzyl,4-(methoxycarbonyl)benzyl, 4-(ethoxycarbonyl)benzyl,3-(dimethylamino-sulfonyl)benzyl,3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl,4-(3-amino-1H-pyrazol-5-yl)benzyl,4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl,3-(morpholin-4-ylsulfonyl)benzyl, 2-(difluoromethyl)benzyl,(3-trifluoromethoxy)benzyl, (2-fluoro-6-trifluoromethyl)benzyl,(2-fluoro-5-trifluoromethyl)benzyl, (2-trifluoromethoxy)benzyl,3-(amino(hydroxyimino)methyl)benzyl, 2-amino-2-(hydroxyimino)ethyl,(6-(N′-hydroxyformimidamido)pyridin-3-yl)methyl,2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl,(4-benzylmorpholin-2-yl)methyl, [(2S)-4-benzylmorpholin-2-yl]methyl,2,3-dihydro-1,4-benzodioxin-6-ylmethyl,[5-(trifluoromethyl)furan-2-yl]methyl, 3-(trifluoromethyl)benzyl,[3-(trifluoromethyl)pyrazin-2-yl]methyl,[4-(trifluoromethyl)pyridin-3-yl]methyl,(5-methoxycarbonylfuran-2-yl)methyl, 5-carboxyfuran-2-ylmethyl,5-(dimethylaminocarbonyl)furan-2ylmethyl,[2-(trifluoromethyl)pyridin-3-yl]methyl, methylcarbonyl, ethoxycarbonyl,tert-butoxycarbonyl or[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl;each R² is independently hydrogen, hydroxy, amino,(hexanylaminocarbonyl)amino, (cyclopentylaminocarbonyl)amino,benzylamino, (cyclohexylaminocarbonyl)amino, methylsulfonylamino,(methyl)carbonylamino, N,N-dimethylaminocarbonyl, (ethyl)carbonylamino,(butyl)carbonylamino, (tert-butyl)carbonylamino,(pentanyl)carbonylamino, (hexanyl)carbonylamino,(methoxymethyl)carbonylamino, cyclobutylcarbonylamino,[2-methoxy(ethoxymethyl)]carbonylamino, (methylsulfonyl)amino,(2-trifluoromethylphenyl)carbonylamino, (cyclohexanyl)carbonylamino,(cyclopentanyl)carbonylamino, (cyclopropanyl)carbonylamino,(phenyl)carbonylamino, bromo, cyano, fluoro, methyl, methoxy,hydroxycarbonyl, methylcarbonyl, pyrrolidinylcarbonyl, aminocarbonyl,methylaminocarbonyl, (2-methoxyethyl)aminocarbonyl,(cyclopropyl)aminocarbonyl, pentylaminocarbonyl,(cyclobutyl)aminocarbonyl, (cyclopentyl)aminocarbonyl,hexanylaminocarbonyl, (cyclohexyl)aminocarbonyl,(4-fluorophenyl)aminocarbonyl, (4-fluorobenzyl)aminocarbonyl,(pyridin-2-ylmethyl)aminocarbonyl, 2-(2-methoxyethoxy)ethoxy,[3-(trifluoromethyl)pyridin-2-yl]oxyl, quinolinyl, phenoxycarbonyl,2-oxochromenyl, 2-oxopyrrolidinyl, morpholinyl, 2-oxopyridinyl,benzyloxyl, [3-(trifluoromethyl)pyridin-2-yl]methoxy,pyridine-2-ylmethoxy, pyridin-2-yloxy, 4-(trifluoromethyl)phenoxy,2-methyl-1,3-thiazol-4-yl, 2-amino-1,3-thiazol-4-yl,6-(dimethylamino)pyridin-3-yl, furan-3-yl, 1H-pyrazol-3-yl,1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl , 5-hydroxy-1H-pyrazol-3-yl,5-methyl-1,2,4-oxadiazol-3-yl, (6-methoxypyridin-3-yl)oxy,1,3-benzodioxol-5-yloxy, 4-fluorobenzyloxy, 3,5-dimethylisoxazol-4-yl,phenoxy, 3-methoxyphenoxy, 4-methoxyphenoxy, 3-morpholin-4-ylphenoxy,4-fluorophenoxy, 4-methoxyphenyl or 4-phenoxyphenyl; or two adjacentR²'s, together with the adjacent carbons to which they are attached,form a fused thiazolyl ring, a fused pyridyl ring or a fused dioxinylring; as a stereoisomer, enantiomer, tautomer thereof or mixturesthereof; or a pharmaceutically acceptable salt or prodrug thereof. 19.The compound of claim 18 wherein J is —O— and K is —CH₂—.
 20. Thecompound of claim 19 selected from:1′-methyl-2′-oxo-N-pentyl-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′carboxamide;1′-(diphenylmethyl)-4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(5-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-7′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(4-fluorophenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-4′-(4-phenoxyphenyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carbonitrile;5′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(diphenylmethyl)-5′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;phenyl1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate;4′,5′-dimethoxy-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′,7′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;6-[2-(2-methoxyethoxy)ethyl]-2,2′,3,3′-tetrahydrospiro[1,4-dioxino[2,3-f]indole-8,8′-furo[2,3-g][1,4]benzodioxin]-7(6H)-one;6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;3′-[2-(fluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile;1′-(4-fluoro-3-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][]1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile;1′-(4-isoxazol-5-ylbenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(4-phenoxyphenyl)-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;3-{[(8S)-2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl]methyl}benzonitrile;(8S)-1′-[(5-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(3-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(S)-1′-(2-oxobutyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;1′-[(4-fluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(3-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8R)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;5′-methyl-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2,1,3-benzothiadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;tert-butyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]piperidine-1-carboxylate;1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[2-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]2′(1′H)-one;1′-{[3-(trifluoromethyl)pyrazin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[4-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-chloropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-methoxypyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(2-methoxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-fluoro-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetonitrile;ethyl2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate;1-(pyrimidin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]2′(1′H)-one;1′-[(4,6-dimethoxypyrimidin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(S)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(R)-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-hexyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2-cyclopropylethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2-ethoxyethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(4-methoxybutyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3-methoxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3-nitrobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(1,3-thiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;(8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one;N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′-(2′H)-yl)methyl]benzenesulfonamide;1′-[3-(morpholin-4-ylsulfonyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2,3-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3,5-difluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(2-chloro-4-fluorobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(1-methyl-1H-benzotriazol-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(3-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2-fluoro-6-trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2-fluoro-5-trifluoromethyL)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2-trifluoromethoxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[2-(2,2,5-trimethyl-1,3-dioxan-2-yl)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;7′-fluoro-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;7′-fluoro-1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;3′-[2-(difluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(5-fluoropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;tert-butyl{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}carbamate;1′-3-(benzyloxy)propyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;ethyl(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate;1′-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-bromo-11′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;methyl3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate;methyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate;1′-[(4-benzylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-{[(2S)-4-benzylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;ethyl4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate;2-[3-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione;(8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;6′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;6′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one;4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′,6′-dimethoxy-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(2′-oxo-2,3-dihydrospiro[furo[2,3-1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)aceticacid;1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylicacid;3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one;2[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile;(8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide;1′-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[4(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]1′(2′H)-yl)methyl]benzoicacid;4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoicacid;N′-hydroxy-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)ethanimidamide;1′-{[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(1′H)-yl)acetohydrazide;1′-{[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3-aminobenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N-{3[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(1′H)-yl)methyl]phenyl}methanesulfonamide;1′-[(1-oxydopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylicacid;1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrobromide;N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide;1′-(piperidin-4-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-{[1-(1-methylethyl)piperidin-4-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-[(1-methylpiperidin-4-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-(morpholin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(4-methylmorpholin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-[(2S)-morpholin-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;(8S)-1′-{[(2S)-4-methylmorpholin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;N,N-dimethyl-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide;N-methyl-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamide;N-(2-aminoethyl)-2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxamidedihydrochloride;N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2H)-yl)methyl]benzamide;N-(2-fluorophenyl)-2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetamide;1′-methyl-4′-(2-oxo-2H-chromen-7-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-(2-oxopyrrolidin-1-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-morpholin-4-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-(2-oxopyridin-1(2H)-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-2-(trifluoromethyl)benzamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)methanesulfonamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclohexanecarboxamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopentanecarboxamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclopropanecarboxamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)benzamide;2-methoxy-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)pentanamide;2,2-dimethyl-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)propanamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)hexanamide;N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)heptanamide;2-(2-methoxyethoxy)-N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)acetamide;1-hexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;1-cyclopentyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;1-cyclohexyl-3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)urea;N-cyclohexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-cyclopentyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-cyclopropyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;1-methyl-4′-(pyrrolidin-1-ylcarbonyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N-(2-methoxyethyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-(4-fluorobenzyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;1′-methyl-2′-oxo-N-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-(4-fluorophenyl)-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;4′-amino-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-hydroxy-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-(pyridin-2-yloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-[2-(2-methoxyethoxy)ethoxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-[4-(trifluoromethyl)phenoxy]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(benzyloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1-methyl-4′-{[3-(trifluoromethyl)pyridin-2-yl]methoxy}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one;1′-methyl-4′-(1H-pyrazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-furan-3-yl1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1-methyl-4′-(1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carbonitrile;1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;1′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(3,5-dimethylisoxazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N,1′-dimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N-cyclobutyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-1,4]benzodioxine-8,3′-indole]-4′-carboxamide;N,N,1′-trimethyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide;4′-(3-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1-methyl-4-phenoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1-methyl-4′-(3-morpholin-4-ylphenoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-[(6-methoxypyridin-3-yl)oxy]-1′-methyl-2,3-dihydrospiro[furo[2,3-1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(1,3-benzodioxol-5-yloxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(4-methoxyphenoxy)-1-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4-(pyridine-2-ylmethoxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4-(4-fluorobenzyloxy)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(4-fluorophenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(4-hydroxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-(3-hydroxypropyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;ethyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate;tert-butyl2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-1′(2′H)-carboxylate;1′-{[(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4′,5′-d]pyran-5-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;6-deoxy-6-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)-D-galactopyranose;1′-cyclopropyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-acetyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[4-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-methyl-4′-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;4′-(5-hydroxy-1H-pyrazol-3-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[4-(3-amino-1H-pyrazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-onehydrochloride;1′-[4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;2′-oxo-1′-(pyridin-2-ylmethyl)-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-5′-carboxamide;1′-[(6-morpholin-4-ylpyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[6-(dimethylamino)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[6-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-({6-[(diphenylmethylidene)amino]pyridin-2-yl}methyl)-2,3-dihydrospiro[furo[2,3-1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(5-morpholin-4-ylpyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-{[5-(dimethylamino)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2-hydroxypyrimidin-5-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(6-aminopyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;N′-hydroxy-N-{5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridin-2-yl}imidoformamide;1′-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;1′-[(2S)-2,3-dihydroxypropyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one;6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carbonitrile;or6-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-2-carboxamide.21. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim 18, as a stereoisomer,enantiomer, tautomer thereof or mixtures thereof; or a pharmaceuticallyacceptable salt or prodrug thereof.
 22. A method of treating pain in amammal, wherein the method comprises administering to the mammal in needthereof a therapeutically effective amount of a compound of claim 18, asa stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or apharmaceutically acceptable salt or prodrug thereof.
 23. The method ofclaim 22, wherein the pain is selected from the group consisting ofneuropathic pain, inflammatory pain, visceral pain, cancer pain, dentalpain, chemotherapy pain, trauma pain, surgical pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,and peripheral nerve injury, and combinations thereof.
 24. The method ofclaim 22, wherein the pain is associated with a disease or conditionselected from HIV, HIV treatment induced neuropathy, heat sensitivity,sarcoidosis, irritable bowel syndrome, Crohns disease, multiplesclerosis, amyotrophic lateral sclerosis, pruritis,hypercholesterolemia, benign prostatic hyperplasia, diabetic neuropathy,peripheral neuropathy, rheumatoid arthritis, osteoarthritis, paroxysmaldystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,Paroxysmal Episodic Pain Disorder, cancer, epilepsy, partial and generaltonic seizures, restless leg syndrome, arrhythmias, ischaemic conditionscaused by stroke or neural trauma, tachy-arrhythmias, atrialfibrillation and ventricular fibrillation.
 25. The method of claim 22wherein the pain is selected from trigeminal neuralgia, post-herpeticneuralgia, eudynia, familial erythromelalgia, primary erythromelalgia,familial rectal pain or fibromyalgia.